The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review)

Abstract

Abstract. Recent data have provided information regarding the profiles of clear cell carcinoma of the ovary (CCC) with adenine-thymine rich interactive domain 1A (ARID1A) mutations. The purpose of this review was to summarize current knowledge regarding the molecular mechanisms involved in CCC tumorigenesis and to describe the central role played by the aberrant chromatin remodeling. The present article reviews the English-language literature for biochemical studies on the ARID1A mutation and chromatin remodeling in CCC. ARID1A is responsible for directing the SWI/SNF complex to target promoters and regulates the transcription of certain genes by altering the chromatin structure around those genes. The mutation spectrum of ARID1A was enriched for C to T transitions. CCC and clear cell renal cell carcinoma (ccRCC) resemble each other pathogenetically. Dysfunction of the ARID1A protein, which occurs with VHL mutations in ccRCC, is responsible for loss of the assembly of the ARID1A-mediated histone H2B complex. Therefore, ARID1A acts as a chromatin remodeling modifier, which stimulates cell signaling that can lead to cell cycle arrest and cell death in the event of DNA damage. The dysfunction of ARID1A may result in susceptibility to CCC carcinogenesis through a defect in the repair or replication of damaged DNA. IntroductionEpithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide. Epidemiology calculations of lifetime risk for EOC are that 1 in 55 women is likely to develop EOC during their lifetime (1). Since EOC is more likely to be advanced stage with unfavorable tumor biology, there are serious limitations to the surgical and oncological treatment available. Therefore, it is crucial to determine the earliest possible diagnosis. Early diagnosis and surgical resection offer patients the best opportunity of excellent long-term survival. On the other hand, patients who either present with metastatic disease or develop distant relapse within 6 months after surgery and chemotherapy have a poor prognosis. Among EOC, clear cell carcinomas of the ovary (CCC) are frequently characterized by chemoresistance and recurrence, resulting in a poor prognosis (2). Since CCC are resistant to conventional cytotoxic (platinum plus taxan-based) chemotherapy, the prognosis is mostly poor (3). In the USA, the incidence of CCC is 5% of all EOC, but the incidence in Japan is reported to be over 20% of all EOC. Thus, Japanese oncologists have focused on investigating the molecular pathogenesis and treatment strategies of CCC.At present, little is known about the molecular genetic mechanisms that are involved in CCC tumorigenesis. Accumulated somatic mutations found in a subset of cancer genes are frequently noted. Such mutations include insertions/deletions (indels) and base substitutions that act as the 'driver mutations' in oncogenesis. These mutations result in the activation of proto-oncogenes (gain of function) or the inhibition of tumor suppressor genes (loss of function) during the process of carcinoge...

Microduplication of the ARID1A gene causes intellectual disability with recognizable syndromic features

“…In our study, we observed that ARID1A duplication in patient-derived fibroblasts slowed cell-cycle progression from G1 to S phase (Figure 4). This result was consistent with the expected role of ARID1A in the cellcycle checkpoint machinery 20 and with the body of oncological literature showing that the overexpression of ARID1A leads to an arrest of cell-cycle progression in G1/S phase. 21 Interestingly, it has been demonstrated that the BAF complex is involved in the proliferation and differentiation of neural stem and progenitor cells.…”

ARID1A knockdown triggers epithelial‐mesenchymal transition and carcinogenesis features of renal cells: role in renal cell carcinoma

“…Regulation of ARID1A in apoptosis evasion remains unclear but may involve inhibition of Fas‐mediated cell death, which was suggested by a previous study showing that suppression of ARID1A by short hairpin RNA inhibited both Fas‐Ab‐induced caspase‐8 cleavage and mitochondrial potential reduction (35). Moreover, there is evidence demonstrating that ARID1A mutation caused dysfunction of histone H2B ubiquitination and restoration of nuclear histone H2B resulted in an aberration of chromatin remodeling proteins, which led to apoptosis evasion (36).…”

Mir-144-3p Promotes Cell Proliferation, Metastasis, Sunitinib Resistance in Clear Cell Renal Cell Carcinoma by Downregulating ARID1A

“…In human tumors, ARID1A was found mutated or missing frequently in carcinomas of the breast, ovarian, lung and kidney in several recent reports [49-51]. Comprehensive molecular studies revealed that ARID1A mutations exist in 3% of ccRCC [52]. But recent articles show that 12% mRNA mutation in genomic alterations (GAs) [10] and 51% protein loss of ARID1A [13] in ccRCC.…”