Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells

作者：Lakshminarasimhan Ranjani; Andreu Vieyra Claudia; Lawrenson Kate; Duymich Christopher E; Gayther Simon A; Liang Gangning^*; Jones Peter A^*

来源：Cancer Letters, 2017, 401: 11-19.

DOI：10.1016/j.canlet.2017.04.040

• ARID1A
• Endometriosis
• Ovarian clear cell carcinoma
• Epigenetics
• Phenotypic transformation

The chromatin remodeler AT-Rich Interactive Domain 1A (ARID1A) is frequently mutated in ovarian clear cell carcinoma (OCCC) and endometriosis precursor lesions. Here, we show that knocking down ARID1A in an immortalized endometriosis cell line is sufficient to induce phenotypic changes indicative of neoplastic transformation as evidenced by higher efficiency of anchorage-independent growth, increased propensity to adhere to collagen, and greater capacity to invade basement membrane extract in vitro. ARID1A knockdown is associated with expression dysregulation of 99 target genes, and many of these expression changes are also observed in primary OCCC tissues. Further, pathway analysis indicates these genes fall within networks highly relevant to tumorigenesis including integrin and paxillin pathways. We demonstrate that the down-regulation of ARID1A does not markedly alter global chromatin accessibility or DNA methylation but unexpectedly, we find strong increases in the active H3K27ac mark in promoter regions and decreases of H3K27ac at potential enhancers. Taken together, these data provide evidence that ARID1A mutation can be an early stage event in the oncogenic transformation of endometriosis cells giving rise to OCCC.

• 出版日期2017-8-10
• 单位上海生物信息技术研究中心