Abstract
Abstract Chemotherapy is the standard care for metastatic disease, in renal cell carcinoma (RCC), the outcome of chemotherapy only prolongs short survival of patients. The reason for the resistance of RCC to chemotherapy is not fully understood, although it has been speculated that overabundance of ATP-binding cassette (ABC)/p-glycoprotein transporter system in RCC might be the reason to repel various chemotherapeutic agents away from the cancer cell. Meanwhile, cancer stem cells (CSC) theory has also focused a significant attention in recent years as a potential explanation for drug resistance and metastasis of RCC. In this study, we demonstrate that drug resistant RCC cells exhibit CSC phenotypes and miR-138 that is significantly downregulated in RCC acted critical role in suppressing CSC phenotype by targeting ABC transporter ABCA13 and oncogenic histone methyltransferase EZH2. Importantly, miR-138 levels were significantly enhanced by treatment of DNA hypomethylating agent (i.e., 5-aza) or histone deactylases inhibitor (i.e., TSA). Epigenetic silencing of tumor-suppressive micro-RNAs has been shown a key oncogenic mechanism for the activation of oncogenes in tumors. Indeed, depletion of miR-138 promoted CSC phenotype followed by enhanced expressions of ABCA13 and EZH2. Furthermore, a novel tumor suppressor DAB2IP can inhibit DNA methyltransferase 1 (DNMT1) activity, which results in miR-138 expression. Taken together, this study identifies the new role of miR-138 in RCC-CSC and unveils a unique regulation of tumor suppressor protein in DNMT1. Overall study provides not only a new biomarker of RCC-CSC and but also potential therapeutic strategy of targeting drug resistant RCC. Citation Format: Eun-Jin Yun, Jiancheng Zhou, Chun-Jung Lin, Elizabeth Hernandez, John Santoyo, Jer-Tsong Hsieh. Epigenetic regulation of miR-138 confers cancer stem cell characteristics of renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3078. doi:10.1158/1538-7445.AM2015-3078
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