Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer

Journal of Advanced Research

Yiren Hu¹  Xiaocen Liu²  Ye Hu³  Kun Lv⁴  Yan Zhang⁵  Hui Yang⁶  Mingzhe Ma⁶  Mingzhe Weng⁶  Hongping Xia⁶  Ping Wan⁶ 

[1] Central Laboratory, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, China;Department of General Surgery, Wenzhou No.3 Clinical Institute of Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, Zhejiang 325000, China;Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200032, China;Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200032, China;Department of Nuclear Medicine, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, China;Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), Wuhu, Anhui 241001, China;

关键词: Gastric cancer;    Chemoresistance;    Hypoxia;    lncRNA;    Ferroptosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

Introduction: Tumors are usually refractory to anti-cancer therapeutics under hypoxic conditions. However, the underlying molecular mechanism remains to be elucidated. Objectives: Our study intended to identify hypoxia inducible lncRNAs and their biological function in gastric cancer (GC). Methods: Differentially expressed lncRNAs were determined by microarray analysis between GC cells exposed to hypoxia (1% O2) and normoxia (21% O2) for 24 h. The expression level of CBSLR was manipulated in several GC cell lines to perform molecular and biological analyses both in vitro and in vivo. Results: We identified a hypoxia-induced lncRNA-CBSLR that protected GC cells from ferroptosis, leading to chem-resistance. Mechanically, CBSLR interacted with YTHDF2 to form a CBSLR/YTHDF2/CBS signaling axis that decreased the stability of CBS mRNA by enhancing the binding of YTHDF2 with the m6A-modified coding sequence (CDS) of CBS mRNA. Furthermore, under decreased CBS levels, the methylation of the ACSL4 protein was reduced, leading to protein polyubiquitination and degradation of ACSL4. This, in turn, decreased the pro-ferroptosis phosphatidylethanolamine (PE) (18:0/20:4) and PE (18:0/22:4) content and contributed to ferroptosis resistance. Notably, CBSLR is upregulated, whereas CBS is downregulated in GC tissues compared to matched normal tissues; and GC patients with high CBSLR/low CBS levels have a worse clinical outcome and a poorer response to chemotherapy. Conclusion: Our study reveals a novel mechanism in how HIF1α/CBSLR modulates ferroptosis/chemoresistance in GC, illuminating potential therapeutic targets for refractory hypoxic tumors.

【 授权许可】

Unknown