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Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 498-508

SiRNA and epigenetic aberrations in ovarian cancer

1 Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran, Iran
3 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Date of Web Publication25-Jul-2016

Correspondence Address:
Hamid Reza Mirzaei
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Post Code: 14176-13151, Tehran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.153661

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 > Abstract 

Ovarian cancer has the most noteworthy lethal rate around gynecologic malignancies, and it is also considered as the fourth most frequent cancer in the woman in world. Two most critical barriers to treatment of ovarian malignancy are absence of early diagnostic markers and advancement of drug resistance after therapy, especially in advanced stages. Various epigenetic changes have been recognized in ovarian cancer. Recent progresses in our understanding of molecular pathogenesis of ovarian malignancy have dramatically provided potential new targets for molecularly targeted therapies. In very recent years, small interfering RNA (siRNA)-mediated gene silencing has been emerging as a novel treatment modality in preclinical studies in the light of its strong gene-specific silencing. Gene suppression mediated by RNA interference (RNAi) significantly suppressed gene expression at the messenger RNA (mRNA) and protein levels. SiRNAs have therapeutic potential for ovarian cancer through various mechanisms. In this review, we not only provide an overview of siRNA designing for epigenetic silencing of genes aberrantly expressed in ovarian cancer but also we will highlight that the epigenetically silenced genes offer new targets for therapeutic approaches based on re-expression of tumor suppressor genes via demethylating and deacetylating drugs.

Keywords: Epigenetics, ovarian cancer, small interfering RNA, therapy

How to cite this article:
Mirzaei H, Yazdi F, Salehi R, Mirzaei HR. SiRNA and epigenetic aberrations in ovarian cancer. J Can Res Ther 2016;12:498-508

How to cite this URL:
Mirzaei H, Yazdi F, Salehi R, Mirzaei HR. SiRNA and epigenetic aberrations in ovarian cancer. J Can Res Ther [serial online] 2016 [cited 2021 Nov 29];12:498-508. Available from: https://www.cancerjournal.net/text.asp?2016/12/2/498/153661

 > Introduction Top

Ovarian cancer

Epithelial ovarian cancer causes a bigger number of deaths than whatever available female reproductive organs malignancy. Epithelial ovarian tumor is the fifth leading reason for malignancy death in women and has the highest death rate of cancer of the reproductive organs.[1] Because of few early indications and an absence of immediate recognition procedures, most patients (>70%) are diagnosed with advanced and late stage disease. Five-year survival rates are shorter than 20% for these advanced stage patients and it has been little enhanced over the past 40 years in spite of developments in chemotherapy.[1],[2] It is a clinically and pathologically heterogeneous disease included serous, mucinous, clear cell, and endometrioid subtypes. Serous tumors are the most well-known subtype. Surgery and chemotherapy are currently the main therapeutic approaches for ovarian cancer. In spite of the fact that the dominant part of patients are at initially responsive to chemotherapy, a large portion of them inevitably create drug-resistant disease.

 > Small Interfering Rna Top

Disclosure of RNA interference (RNAi) has been a standout amongst the most critical discoveries in the most recent 10 years. As of late, siRNA-mediated gene silencing is starting to show significant guarantee as another treatment modality in preclinical studies in view of its strong gene-specific silencing. Not so long ago, delivery of siRNA in vivo was considered as a significant barrier in its utilization as a restorative modality.[3]

 > Epigenetics Top

Epigenetics is normally characterized as a heritable and reversible change in gene expression that is not joined by a change in the DNA sequence.[4] There are three real epigenetic changes: Those happening at the DNA level (DNA methylation), chromatin level (chromatin remodeling), and microRNAs (miRNAs).[5] DNA methylation is a chemical driven concoction change to the DNA arrangement that most normally happens in the typical mammalian genome, methylation happens just at cytosines 5' to guanosines and the CpG dinucleotide has been dynamically exhausted from the eukaryotic genome over advancement.[6] The remaining CpG in vertebrates have a high recurrence of methylation, which may encourage chromatin courses of action to render the vast majority of the genome late duplicating and suppressed for the translation of rehashed locales, for example, Alu substitutions and transposons.[7] By complexity, little (0.5 to a few kb) extends of DNA, or 'CpG islands, hold the normal recurrence of CpGs. These territories are “secured” from methylation and are placed in the proximal promoter areas of ~ 40–50% of human genes.[6] This absence of methylation could be an essential for animated translation, as outlined by two ordinary special cases to this circumstance. Completely methylated CpG islands are discovered just in the promoters of quieted alleles for chose engraved autosomal genes and various hushed genes on the inactivated X-chromosomes of females. A developing number of tumor genes are constantly distinguished that harbor thick methylation in ordinarily unmethylated promoter CpG islands.[8],[9] The primary suggestions that this hypermethylation may practically help misfortune of gene function created extensive incredulity that continued, considerably after this occasion was connected with truant expression of an exemplary tumor suppressor gene.[10] It could be contended that methylation is not answerable for starting gene silencing, however, an auxiliary occasion that denotes the methodology. Chromatin remodeling happens by means of the alteration of histone deposits by enzymes principally on the N-terminal tails and eventually influences the cooperation of DNA with chromatin altering proteins. Both DNA methylation and histone modifications are connected with silencing discriminating tumor suppressor genes and enacting oncogenes included in cancer.[5] [Figure 1] demonstrates epigenetic modifications in human ovarian cancer.
Figure 1: Schematic diagram of epigenetic modifications in human ovarian cancer

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DNA methylation

DNA methylation is one of the instruments suppressing gene expression. In mammalian cells, DNA methylation alludes to the methylation of deoxycytosine bases at the 5 position to form deoxymethylcytosine. Nearly all deoxymethylcytosine is found in CG dinucleotides, and almost nearly 70–80% of CG pairs are methylated. Most unmethylated CG pairs are found in GC-rich arrangements termed CpG islands, while most of the methylated pairs are found in the rest of the DNA. CpG islands encompass different multiple transcription factor binding sites, and serve as promoters for the related gene. Almost all “housekeeping” genes, and some tissue-specific genes, encompass CpG islands. Almost, a large portion of mammalian genes are connected with CpG islands.[11],[12] Progressive DNA methylation is thought to help ordinary maturing and to different pathologic states, encompass malignancy. Methylation at CpG locales influences transcription by enlisting methyl-CpG binding domain proteins that function as adaptor between methylated DNA and chromatin modifying proteins.[13],[14],[15] DNA methylation is managed by a group of DNA methyltransferases (DNMTs) that encompass DNMT1, DNMT3A, and DNMT3B. Every one of the three DNMTs are embryonic deadly in knockout mice models. Nonetheless, DNMT3A and 3B are paramount for patterning of DNA methylation during embryogenesis, after which DNMT1 acts as a maintenance methyltransferase.[16],[17] However, the distinct parts of the DNMT enzymes have been tested in malignancy models: Some examiners have demonstrated that serious consumption of DNMT1 produces (a) insignificant reductions in general DNA methylation and promoter methylation and (b) undetectable changes in expression of silenced tumor-suppressor genes.[18],[19],[20],[21]

Chromatin remodeling

Chromatin comprises of nucleosomes, each one holding 147 bp of DNA wrapped around an octomer of the center histone proteins H3, H4, H2a, and H2b.[22] The tertiary structure of chromatin and the action of the partnered gene is specifically intervened by various changes of the chromatin segments. Particularly, the chromatin structure around unmethylated CpG island promoters in ordinary cells permit proteins that elevate to gene expression. Inasmuch as a methylated CpG island in a cancer cell is connected with hard compacted chromatin which forestalls protein access and resulting gene expression.[23] The center histones are predominantly globular aside from their N-terminal tails which are unstructured. A striking specification of histones, and especially of their tails, is the vast number and kind of modified residues they have. There are presently eight described classes of histone alterations, acetylation, lysine methylation, arginine methylation, phosphorylation, ubiquitylation, sumoylation, ADP ribosylation, deamination, and proline isomerization, which function to direct different methodologies, for example, translation, repair, replication, and development.[24] These changes are steered to histone deposits by different histone-modifying catalysts, and compounds that demonstrate to evacuate the change have additionally been distinguished.


Epigenetics has been as of late reached out to miRNA. They are single-stranded RNA molecules of about 21–23 nucleotides long, which manage gene expression. miRNA are encoded by genes that are deciphered from DNA not made as protein (noncoding RNA); rather they are prepared from essential transcripts known as pri-miRNA to short stem-loop structures called pre-miRNA and at last to useful miRNA. Adult miRNA molecules are part of the way integral to one or more messenger RNA (mRNA) particles, and their principle function is to downregulate gene expression.[25] Rising is an idea coordinating genomic methylation, histone modifications, and the impacts of miRNAs. On one side, the expression of certain miRNA is controlled by DNA methylation and chromatin modifications. Therefore, miRNAs could influence methylation apparatus and expression of proteins included in histone modifications. Altogether, these components decide the statement of genes and the phenotype. Epigenetic silencing of miRNA and miRNAs focusing on histone deacetylases (HDACs) have been depicted to assume a part in malignancy. Epigenetic silencing of miRNAs with tumor suppressor offers by CpG island hypermethylation is rising as a regular sign of human tumors.[26],[27]

 > Epigenetic Aberrations in Ovarian Cancer Top

The involvement of epigenetic aberrations in the development and progression of tumors is now well-established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes.

Hypermethylated genes

CpG island hypermethylation is an ordinary phenomenon in ovarian cancer.[28],[29] Reports of hypermethylation in malignancy far outnumber the reports of hypomethylation in cancer. There are a few defensive systems that keep the hypermethylation of the CpG islands. These encompass active transcription, active demethylation, replication timing, and local chromatin structure structure access to the DNMT.[30],[31] Besides classical tumor suppressors that may be hypermethylated in ovarian cancer such as BRCA1, p16, and MLH1; examples of other genes hypermethylated in ovarian cancer include the putative tumor suppressors OPCML and RASSF1A; the imprinted genes ARHI (ARLTS1), PEG3, DLEC1, ARL11, and TCEAL7; the proapoptotic genes LOT1, DAPK, TMS1/ASC, and PAR-4; the cell adhesion–associated genes ICAM-1 and CDH; the cell signaling gene HSulf-1; and the genome stability gene PALB2.[29],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44] Recently discovered candidate tumor suppressor genes hypermethylated in ovarian cancer are SPARC, ANGPTL2, and CTGF.[45],[46],[47] In many cases, the practical impacts of gene silencing on ovarian cancer pathogenesis are however not known. A standout amongst the most considered genes in ovarian cancer is BRCA1 because of its part in both inherited and sporadic types of this disease.[48] Studies investigating BRCA1 hypermethylation report methylation in 5–24% of epithelial ovarian cancers.[48],[49],[50] A late study investigating the diverse methylation profiles of sporadic and genetic ovarian tumor indicated BRCA1 to be methylated in 14% of sporadic tumors, however never in innate ovarian cancer.[51] In prior studies, hypermethylation of the BRCA1 promoter was accounted for to run from 5 to 40% in sporadic ovarian cancer. BRCA1 methylation is unequivocally connected with misfortune of BRCA1, RNA, and protein and significantly related with poor result in sporadic disease.[28],[52] No correspondence of BRCA1 methylation with histological subtypes or stage has been found yet.[53],[54] BRCA2 promoter methylation is once in a while found in sporadic nongenetic ovarian cancers.[52],[54] Interestingly, gene methylation examples are frequently connected with molecular, clinical, and obsessive characteristics of ovarian carcinomas. Analyzing methylation status of SFRP1, 2, 4, and 5; SOX1; PAX1; and LMX1A between patients with benign, borderline, and malignant ovarian cancer demonstrated that methylation rates were most astounding in ovarian cancer patients and diminished dynamically in patients with an outskirt harm and nonmalignant ovarian tissue.[55] Methylation of the embryonic developmentally controlled genes HOXA10 and HOXA11 was discovered to be profoundly discriminative between ordinary and harmful ovarian tissue.[56] Additionally, methylation microarrays have been utilized to look at global DNA hypermethylation in ovarian cancer.[57] It has been showed that ovarian cancer holds an expansive number of hypermethylated loci and that the level of abnormal methylation is associated with ovarian tumor movement. Another investigation revealed that 956 loci of the 7,776 CpG islands were hypermethylated in the tumor contrary to typical control tissue.[57] DNA methylation profiles of the ovarian cancer additionally demonstrated clear differences between histological subtypes.[58] For instance, distorted methylation of the promoters of 14-3-3 sigma, TMS1, and WT1 is a more common in cell ovarian cancer than in other histological types [Table 1].[50],[59],[60],[61],[62],[63]
Table 1: Overview of hypermethylated genes in human ovarian cancer

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Hypomethylated genes

Not just is the generally contemplated hypermethylation of CpG islands in promoter locales connected with carcinogenesis, additionally hypomethylation of certain different parts of the genome is a regular cancer associated ordinary.[104],[105],[106] There are, nonetheless, constrained illustrations of particular gene initiation by hypomethylation in ovarian cancer. Genes overexpressed in ovarian cancer companionship with promoter hypomethylation incorporate MCJ (methylation-controlled DNA J gene), synuclein-γ (SNCG), TRAG-3, and BORIS (brother of the regulator of imprinted sites).[107],[108],[109],[110],[111] Other ovarian cancer hypomethylated genes are insulin-like growth factor-2 (IGF-2) and claudin-4. Retrotransposons, a real class of center monotonous groupings, have been identified as potential focuses of hypomethylation.[112],[113],[114],[115] Retrotransposons are arranged into three subtypes: Long interspersed elements (LINEs), short interspersed elements (SINEs), and long terminal repeat retrotransposons (LTRs).[116] The LINE-1 methylation example was hypomethylated in epithelial ovarian cancer examples in 95% of cases.[117] The methylation levels were easier contrasted and delegate control tissue.[117],[118] A diminishing in the level of LINE-1 methylation was connected with histological subtypes; mucinous tumors had higher methylation levels than endometrioid. Hypomethylation frequently involves satellite 2 (Sat2) DNA in the juxta centromeric part of chromosome 1 and 16 in ovarian cancers.[119] Hypomethylation of both chromosomes 1 satellite 2 and chromosome 1 satellite α expanded significantly from benign to ovarian cancer tissue. Serous and endometrioid tumors indicated higher hypomethylation levels than mucinous tumors.[120] Moreover, far reaching hypomethylation was more pervasive in tumors of progressed stage or high grade [Table 2].
Table 2: Overview of hypomethylated genes in human ovarian cancer

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The most as of late uncovered epigenetic sensation is posttranscriptional gene downregulation by small (21–23 nucleotides length), non-protein-coding RNA molecules known as miRNAs.[128],[129] Tissue-specific miRNAs have been reported. Overexpression of mir-200a, mir-200b, mir-200c, and mir-141 has been portrayed in ovarian cancer.[130],[131],[132],[133],[134],[135],[136],[137],[138],[139],[140] Then again, mir- 199a, mir-140, mir-145, and mir-125b1 were around the most downregulated ones.[141] miRNA marks of ovarian cancer could be useful to recognize the tumors dependent upon their histological subtype; mir200b and mir-141 were upregulated in endometrioid and serous subtypes.[130] Besides, the endometrioid histotypes appear to show the upregulation of three extra miRNAs: mir-21, mir-203, and mir-205. Nineteen miRNAs were downregulated in all the three histotypes in correlation with ordinary tissue, inasmuch as mir-145 was downregulated in both serous and clear cell carcinomas and mir-222 in both endometrioid and clear cell carcinomas.[130] Noteworthy downregulation of mir-34c, mir-422b, mir-143, and mir-145, and in addition expanded expression of mir-29a and mir- 29b, was seen in patients with BRCA1/2 anomalies.[142],[143] Interestingly, the levels of mir-21, mir-203, and mir-205 that are upregulated in ovarian carcinomas contrasted with ordinary tissue were significantly expanded in the wake of demethylating treatment, proposing that the hypomethylation could be the instrument answerable for their overexpression [Table 3] and [Table 4].
Table 3: Overview of upregulated miRNAs in human ovarian cancer

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Table 4: Overview of downregulated miRNAs in human ovarian cancer

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Histone modifications

Notwithstanding redistributions of DNA methylation patterns, an alternate epigenetic abnormality in ovarian cancer atypical modifications of histones and dysregulated expression of histone-modifying enzymes. Numerous covalent posttranslational modifications of the histone tails have been reported, of which acetylation, methylation, and phosphorylation are most overall portrayed.[150],[151] Histone modifications contribute typical ovarian functions; encompass estrogen blend, folliculogenesis, and luteal phase action.[152] Ovarian cancer cells, nonetheless, significantly change their expression of chromatin-altering proteins.[153] Like DNA methylation, histone modifications can assume a part in silencing of tumor suppressor genes. Atypical expression of class III β-tubulin protein, silencing of survivin, decrease of PACE4 expression, and absence of claudin-3 expression are interfaced to histone alterations in ovarian carcinogenesis.[154],[155],[156],[157] Correspondingly, changed histone alteration of the promoter loci was discovered answerable for the silencing of the GATA4 and GATA6 translation calculates in ovarian cancer cell lines.[158] This was connected with resulting loss of a target gene, the tumor suppressor disabled-2.[158] Histone acetylation is frequently connected with expanded translation and is managed by two restricting classes of compounds: Histone acetyltransferases and HDACs. HDACs1–3 have been indicated to be overexpressed in ovarian cancer tissue and are thought to assume a part in ovarian carcinogenesis.[159] Two genes upregulated by histone acetylation incorporate the tumor suppressor Rb and the cyclin-dependent kinase inhibitor (CDKN1) [Table 5] and [Table 6].[160]
Table 5: Overview of gene downregulations by histone modifications in human ovarian cancer

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Table 6: Overview of gene upregulations by histone modifications in human ovarian cancer

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 > Epigenetic Therapy Top

The initiation and advancement of malignancy is controlled by both genetic and epigenetic events. Contrary to genetic modifications which are very difficult to reverse, epigenetic aberrations are conceivably reversible, permitting the tumor cell population revert to a more typical state.[161],[163] In respect to emerging of various drugs that target particular proteins including the epigenetic regulators, the usage of epigenetic targets is rising as a successful and valuable approach to chemotherapy as well as chemoprevention of malignancy.[163],[164] Complex epigenetic patterns encompass DNA methylation, histone modifications, and miRNA abnormality help ovarian malignancy advancement and drug resistance. Though genetic change, deletion, or allelic losses will be fixed and irreversible, epigenetic irregularities can possibly be corrected.[165],[166] Subsequently, reversing epigenetic events could be a guaranteeing treatment modality. In this respect, inhibitors of DNMTs or HDAC action are presently being considered.[95],[96],[97],[98],[167],[168] [Table 7] represents an overview of some DNMT and HDAC inhibitors in human ovarian cancer.
Table 7: Overview of some DNMT and HDAC inhibitors in human ovarian cancer

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 > Therapeutic Implication of Sirna Top

SiRNA as a promising novel therapeutic molecule could be used in epigenetic-based cancer therapy. Gene suppression mediated by RNAi significantly suppressed genes expression at the mRNA and protein levels. This suggests that gene suppression mediated by an RNAi strategy may become a novel approach for treating advanced type of cancers like ovarian cancer.


Mutations in the BRCA1 gene happen in 5% of ovarian malignancy cases in the all-inclusive community,[179] and inheritance of DNA repair deficiency helps 10% of all ovarian malignancy.[180] Additionally, numerous ovarian malignancies fail to express BRCA1 because of epigenetic aberrant.[64] There are various studies demonstrating that breast malignancy tumors that examine as defective in DNA repair are likewise sensitive to poly (adp-ribose) polymerase (PARP) inhibitors.[181] Inhibition of the DNA repair enzyme poly (adp-ribose) polymerase 1 (Parp1) with small molecule has been shown to be a convincing treatment for ovarian malignancy with BRCA mutations. Goldberg et al., investigated in vivo administration of siRNA to Parp1 in mice models of ovarian cancer. A special part of the lipid-like materials known as lipidoids is demonstrated to delivery siRNA to scattered murine ovarian carcinoma allograft tumors taking after intraperitoneal injection (IP). SiParp1 hinders cell malignancy, fundamentally by actuation of apoptosis, in BRCA1-deficient cells both in vitro and in vivo. Also, the treatment enlarges the survival of mice-bearing tumors determined from BRCA1-deficient ovarian cancer cells not from BRCA1 wild-type cells, affirming the proposed system of synthetic lethality.[182]


Confirmation is amassing to help a part for the insulin-like malignancy factor family in human carcinogenesis, and as of late utilizing microarray expression examination it showed overexpression of the IGF-2 gene in exceptional stage epithelial ovarian cancers.[183] Another study inspected the part of IGF indicating pathway in the reaction of ovarian cancer cells to Taxol and assessed the centrality of this pathway in human epithelial ovarian cancer. The impact of Taxol drugs on AKT actuation in A2780 ovarian carcinoma cells was assessed utilizing antibodies particular for phosphorylated AKT. To study the pill safe phenotype, a Taxol-safe cell line, HEY-T30, derived from HEY ovarian cancer cells, was produced. IGF-2 expression was measured by continuous PCR. An IGF1R inhibitor, NVP-AEW541, and IGF2 siRNA were utilized to assess the impact of IGF pathway restraint on expansion and Taxol sensitivity.[184]

Results showed that Taxol-induced AKT phosphorylation is necessary for IGF1R tyrosine kinase activity and is linked to IGF-2 upregulation. In comparison to susceptible cells, insensitive cells had higher IGF-2 expression and blocking of IGF pathway returned susceptibility to Taxol. It was also revealed that high IGF-2 tumor expression is correlated with advanced stage and tumor grade and reduced disease-free survival.

Claudin-3 and claudin-4

Claudin proteins represent an expansive group of essential membrane proteins vital for tight intersection arrangement and function. Past studies have uncovered that claudin-3 and claudin-4 proteins are exceptionally overexpressed in ovarian cancer.[127],[185] In one study, Huang et al., have produced human ovarian surface epithelial (HOSE) cells constitutively communicating wild-type claudin-3 and claudin-4. Expression of these claudins in HOSE cells expanded cell intrusion and motility as measured by Boyden chamber examines and wound-mending examinations. Then again, siRNA-mediated knockdown of claudin-3 and claudin-4 expression in ovarian cancer cell lines diminished intrusion.[185] Claudin expression likewise expanded cell survival in HOSE cells yet completed not essentially influence cell burgeoning. In addition, the claudin-connection ovarian epithelial cells were found to have expanded lattice metalloproteinase-2 (MMP-2) action showing that claudin-mediated expanded intrusion could be intervened through the actuation of MMP proteins. Notwithstanding, siRNA mediated of claudins in ovarian cancer cell lines completed, donot have a critical impact on the high endogenous MMP-2 movement show in these cells, indicating that dangerous cells have elective or extra pathways to completely actuate MMP-2. Taken together, their effects propose that claudin overexpression may push ovarian tumorigenesis and metastasis through expanded intrusion and survival of tumor cells.[186]


Histone acetylation/deacetylation controls chromatin action and ensuing gene transcription.[187],[188] Late studies showed the actuation of HDACs in different human cancer; then again, the expression and function of HDACs in ovarian cancer are not completely understood.[189] In one study, the immunohistochemical expression of HDAC1, HDAC2, and HDAC3 utilizing tissues acquired from 115 samples of ovarian cancer and contrasted it and that of Ki-67 (a malignancy marker), p21, and E-cadherin and clinicopathological parameters was inspected. Likewise, it was dissected the impact of particular siRNA for HDAC1, HDAC2, and HDAC3 on the expression of cell cycle-related molecules and E-cadherin to clear up the useful contrast around the 3 HDACs. The outcomes demonstrated that the immunohistochemical expression of nuclear HDAC1, HDAC2, and HDAC3 proteins expanded stepwise in benign, borderline, and malignancy tumors. The expression of HDAC1 and HDAC2 was connected with Ki-67 expression and that of HDAC3 was contrarily connected with E-cadherin representation. Around the HDAC3 analyzed, just HDAC1 was connected with a poor result, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in connection with apoptosis. A particular siRNA for HDAC1 fundamentally diminished the proliferation of ovarian carcinoma cells through downregulation of cyclin A expression; however, siRNA for HDAC3 decreased the cell movement with enhance E-cadherin expression. Their outcomes proposed that HDAC1 assumes a critical part in the proliferation of ovarian cancer cells, while HDAC3 roles in cell adhesion and movement. Subsequently, particular therapeutic methodologies ought to be acknowledged as stated by the HDAC subtypes.[190]


The synucleins are a group of small cytoplasmic proteins that are communicated overwhelmingly in neurons. As of late, their expression has been discovered likewise in numerous human cancers. SNCG mRNA is communicated in a considerable extent of ovarian cancer and demethylation is a paramount occasion in unusual SNCG expression in a large portion of these cases.[109] In one of the studies, the impacts of SNCG downregulation by RNAi on the clonogenicity and invasiveness of MCF-7 breast cancer cells was explored. It utilized four sets of SNCG-specific siRNAs which were planned and cloned into the pGPU6 plasmid for presentation into a MCF-7 cell line. The SNCG knockdown efficacies of the four siRNAs were analyzed utilizing the reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. As stated by the outcomes of this study, it was presumed that SNCG concealment mediated by RNAi altogether smothered SNCG expression at the mRNA and protein levels, proposing that SNCG expression mediated by RNAi technique may become a novel methodology for treating propelled breast and ovarian cancer.[191]


Polycomb complex protein Bmi-1 (B lymphoma Mo-MLV insertion region 1 homolog) otherwise called polycomb aggregation RING finger protein 4 (PCGF4) or RING finger protein 51 (RNF51) is a protein that in human is encoded by the Bmi1 gene.[192],[193]Bmi1 has been accounted for as an oncogene by controlling p16 and p19, which are cell cycle inhibitor genes. The knockdown of Bmi-1 could adequately suppress malignancy cell proliferation and tumorigenicity in a few cancers. In one study, the mRNA and protein expression levels of Bmi-1 in the human ovarian carcinoma cell line OVCAR-3 were downregulated by Bmi-1 siRNA, as affirmed by ongoing PCR and Western blot. Focusing on Bmi-1 with siRNA hindered Bmi-1 mRNA in excess of fivefold contrasted and the control cells, and restrained Bmi-1 protein expression in excess of three-fold contrasted and control cells. The suitability of the OVCAR-3 ovarian cancer cell line was decreased by Bmi-1 mRNA contrasted with control cells. Telomerase movement was diminished 22.73% (from 0.33 to 0.255) by Bmi-1 siRNA therapy contrasted with control cells. As Bmi-1 siRNA discouraged telomerase action, cell immortalization may be averted; accordingly, silencing Bmi-1 may be a potential therapy to oversee ovarian cancer.[194]

 > Conclusion Top

It is progressively apparent that epigenetics plays a prominent role in ovarian malignancy, and a more prominent understanding of this sensation will probably prompt and tremendously enhance diagnostic and therapeutic intercessions. Several epigenetic changes have shown promise for diagnostic, prognostic, and predictive function of ovarian cancer, but still need further validation. siRNAs have therapeutic potential for ovarian cancer through various mechanisms. Gene suppression mediated by siRNAs significantly suppressed gene expression at the mRNA and protein levels. This suggests that gene suppression mediated by siRNAs strategy may become a novel approach for treating ovarian cancer.

 > References Top

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]

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