Hypoxia induces hepatocellular carcinoma metastasis via the HIF-1α/METTL16/lnc-CSMD1-7/RBFOX2 axis

Yingchao Wang; Yong Yang; Ye Yang; Yuan Dang; Zhiting Guo; Qiuyu Zhuang; Xiaoyuan Zheng; Fei Wang; Niangmei Cheng; Xiaolong Liu; Wuhua Guo; Bixing Zhao

doi:10.1016/j.isci.2023.108495

Hypoxia induces hepatocellular carcinoma metastasis via the HIF-1α/METTL16/lnc-CSMD1-7/RBFOX2 axis

iScience. 2023 Nov 19;26(12):108495. doi: 10.1016/j.isci.2023.108495. eCollection 2023 Dec 15.

Authors

Yingchao Wang^{1

2}, Yong Yang^{1

2

3}, Ye Yang^{1

2}, Yuan Dang³, Zhiting Guo^{1

2}, Qiuyu Zhuang^{1

2}, Xiaoyuan Zheng¹, Fei Wang¹, Niangmei Cheng¹, Xiaolong Liu^{1

2}, Wuhua Guo^{2

4}, Bixing Zhao^{1

2}

Affiliations

¹ The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P.R. China.
² Mengchao Med-X Center, Fuzhou University, Fuzhou 350116, P.R. China.
³ Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China.
⁴ Department of Interventional Radiology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China.

Abstract

Hypoxic microenvironment is clinically associated with metastasis and poor prognosis of numerous cancers. The mechanisms by which intratumoral hypoxia regulates metastasis are not fully understood. Our study identifies a downregulation of Lnc-CSMD1-7 in hepatocellular carcinoma (HCC) and correlated with poor prognosis of HCC patients. Lnc-CSMD1-7 negatively regulated HCC cell migration and invasion in vitro and suppressed lung metastasis in vivo. Mechanistically, Lnc-CSMD1-7 directly binds to RBFOX2, thereby affecting RBFOX2-regulated alternative splicing in epithelial and mesenchymal-specific events. More importantly, hypoxic microenvironment and m6A methylation mediate the downregulation of Lnc-CSMD1-7 expression. Specifically, hypoxia transcriptionally upregulates the expression of the m6A methyltransferase METTL16 via HIF-1α, and METTL16 directly binds to Lnc-CSMD1-7 and downregulates the RNA stability of Lnc-CSMD1-7 via m6A methylation, ultimately promoting HCC metastasis. Our findings highlight the regulatory function of the METTL16/Lnc-CSMD1-7/RBFOX2 axis in modulating hypoxia-induced HCC progression, which may provide potential prognostic and therapeutic targets for HCC treatment.

Keywords: Cancer; Epigenetics; Molecular biology.