Yang Yang, Luo Jingjing, Wang Zhongyu, Liu Kaiyue, Feng Keyi, Wang Fang, Mei Yide
Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.
School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
Cancer Res. 2025 Feb 17;85(4):723-738. doi: 10.1158/0008-5472.CAN-24-1630.
The tumor microenvironment plays a pivotal role in the metabolic reprogramming of cancer cells. A better understanding of the underlying mechanisms regulating cancer metabolism could help identify potential therapeutic targets. Here, we identified circEPB41(2) as a metabolically regulated circular RNA that mediates lipid metabolism in hepatocellular carcinoma (HCC). circEPB41(2) was induced in response to glucose deprivation via HNRNPA1-dependent alternative splicing. Upregulation of circEPB41(2) led to enhanced lipogenic gene expression that promoted lipogenesis. Mechanistically, circEPB41(2) cooperated with the N6-methyladenosine demethylase FTO to decrease the mRNA stability of the histone deacetylase sirtuin 6, thereby increasing histone H3 lysine 9 acetylation and histone H3 lysine 27 acetylation levels to activate lipogenic gene expression. Silencing of circEPB41(2) inhibited both in vitro proliferation of HCC cells and in vivo growth of tumor xenografts. Clinically, circEPB41(2) was elevated in HCC, and high circEPB41(2) expression was associated with poor patient prognosis. Overall, this study reveals that circEPB41(2) is an important regulator of lipid metabolic reprogramming and indicates that targeting the circEPB41(2)-FTO-sirtuin 6 axis could represent a promising anticancer strategy for treating HCC. Significance: circEPB41(2) is induced by glucose deprivation and mediates epigenetic alterations to drive lipogenesis and tumor growth in hepatocellular carcinoma, suggesting circEPB41(2) could be a potential therapeutic target in liver cancer.
肿瘤微环境在癌细胞的代谢重编程中起着关键作用。更好地理解调节癌症代谢的潜在机制有助于确定潜在的治疗靶点。在此，我们鉴定出circEPB41(2)是一种受代谢调控的环状RNA，其介导肝细胞癌（HCC）中的脂质代谢。circEPB41(2)通过HNRNPA1依赖性可变剪接响应葡萄糖剥夺而被诱导。circEPB41(2)的上调导致促进脂肪生成的脂肪生成基因表达增强。机制上，circEPB41(2)与N6-甲基腺苷去甲基化酶FTO协同作用，降低组蛋白去乙酰化酶sirtuin 6的mRNA稳定性，从而提高组蛋白H3赖氨酸9乙酰化和组蛋白H3赖氨酸27乙酰化水平，以激活脂肪生成基因表达。circEPB41(2)的沉默抑制了HCC细胞的体外增殖和肿瘤异种移植的体内生长。临床上，circEPB41(2)在HCC中升高，且circEPB41(2)高表达与患者预后不良相关。总体而言，本研究揭示circEPB41(2)是脂质代谢重编程的重要调节因子，并表明靶向circEPB41(2)-FTO-sirtuin 6轴可能是治疗HCC的一种有前景的抗癌策略。意义：circEPB41(2)由葡萄糖剥夺诱导，并介导表观遗传改变以驱动肝细胞癌中的脂肪生成和肿瘤生长，提示circEPB41(2)可能是肝癌的潜在治疗靶点。
