ZC3H13 Inhibits the Progression of Hepatocellular Carcinoma through m6A-PKM2-Mediated Glycolysis and Enhances Chemosensitivity

Qibo Wang; Haichuan Xie; Hao Peng; Jianjian Yan; Limin Han; Gang Ye

doi:10.1155/2021/1328444

ZC3H13 Inhibits the Progression of Hepatocellular Carcinoma through m⁶A-PKM2-Mediated Glycolysis and Enhances Chemosensitivity

J Oncol. 2021 Dec 30:2021:1328444. doi: 10.1155/2021/1328444. eCollection 2021.

Authors

Qibo Wang¹, Haichuan Xie², Hao Peng¹, Jianjian Yan¹, Limin Han³, Gang Ye²

Affiliations

¹ Department of Hepatobiliary Surgery, Pingxiang People's Hospital of Southern Medical University, Pingxiang, Jiangxi 337055, China.
² Department of Hepatobiliary Surgery, People's Hospital of Changshou Chongqing, Chongqing 401220, China.
³ Department of Endocrinology, People's Hospital of Changshou Chongqing, Chongqing 401220, China.

Abstract

Objective: N⁶-Methyladenosine (m⁶A) is the most prevalent RNA epigenetic modulation in eukaryotic cells, which serves a critical role in diverse physiological processes. Emerging evidences indicate the prognostic significance of m⁶A regulator ZC3H13 in hepatocellular carcinoma (HCC). Herein, this study was conducted for revealing biological functions and mechanisms of ZC3H13 in HCC.

Methods: Expression of ZC3H13 was examined in collected HCC and normal tissues, and its prognostic significance was investigated in a public database. Gain/loss of functional assays were presented for defining the roles of ZC3H13 in HCC progression. The specific interactions of ZC3H13 with PKM2 were validated in HCC cells via mRNA stability, RNA immunoprecipitation, and luciferase reporter and MeRIP-qPCR assays. Moreover, rescue experiments were carried out for uncovering the mechanisms.

Results: ZC3H13 expression was downregulated in HCC, and its loss was in relation to dismal survival outcomes. Functionally, overexpressed ZC3H13 suppressed proliferation, migration, and invasion and elevated apoptotic levels of HCC cells. Moreover, ZC3H13 overexpression sensitized to cisplatin and weakened metabolism reprogramming of HCC cells. Mechanically, ZC3H13-induced m⁶A modified patterns substantially abolished PKM2 mRNA stability. ZC3H13 facilitated malignant behaviors of HCC cells through PKM2-dependent glycolytic signaling.

Conclusion: Collectively, ZC3H13 suppressed the progression of HCC through m⁶A-PKM2-mediated glycolysis and sensitized HCC cells to cisplatin, which offered a fresh insight into HCC therapy.