Abstract 5841: Discovery of a novel epigenetic regulatory axis that mediates sorafenib's antineoplastic activity

• Published in: Cancer research (Chicago, Ill.) Vol. 82; no. 12_Supplement; p. 5841
• Main Authors: Wei, Tianzi, Wang, Hao, Lin, Risheng, Li, Yueming, Lu, Yi, Zhang, Jian
• Format: Journal Article
• Language: English
• Published: 15.06.2022
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-5841

Abstract As a multi-kinase inhibitor, sorafenib has been widely used to treat advanced hepatocellular carcinoma patients since 2007. Sorafenib, however, is associated with severe drug adverse effects and drug resistance. Therefore, the strategies to improve the antineoplastic effects of sorafenib are urgently needed. In this study, we observed that metallothionein-1G (MT1G), was significantly activated by sorafenib and mediated sorafenib’s antineoplastic activity both in vitro and in vivo. Our study also proved that sorafenib effectively inhibited the activity of several critical enzymes required for maintaining methylation level in hepatoma cells to activate MT1G. In addition, the ATAC-seq results demonstrated that the promotor region of MT1G become more accessible upon the treatment of sorafenib, which may make a few key transcription factors easier to bind to the promoter region of MT1G to initiate the transcription. Finally, next-generation sequencing (NGS) results showed that the expression of two tumor associated genes: KLF4 and CA9, were significantly altered by MT1G overexpression. KLF4 was required to bind to the promotor region of CA9 and then inhibit the expression of CA9, a hypoxia-induced gene involved in modulating tumor microenvironment. The decrement of CA9 expression was related to hepatoma cells suppression. Taken together, we deduce that MT1G-KLF4-CA9 axis is a potential novel pathway to suppress hepatoma cell progression regulated by sorafenib. The regulation of MT1G-KLF4-CA9 is plausible to synergize with sorafenib to improve the therapeutic effects. Supported by NSFC projects 81773146, 81972766, 81972420, 82173336; Shenzhen Science and Technology Commission Project JCYJ20180302174235893; Sanming Project of Medicine in Shenzhen SZSM202003009; Guangdong Basic and Applied Basic Research Foundation 2021A1515012161; and Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research (2017B030301018) Citation Format: Tianzi Wei, Hao Wang, Risheng Lin, Yueming Li, Yi Lu, Jian Zhang. Discovery of a novel epigenetic regulatory axis that mediates sorafenib's antineoplastic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5841.