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

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% O) and normoxia (21% O) for 24 h. The expression level of was manipulated in several GC cell lines to perform molecular and biological analyses both in vitro and .

RESULTS

We identified a hypoxia-induced lncRNA- that protected GC cells from ferroptosis, leading to chem-resistance. Mechanically, interacted with YTHDF2 to form a /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, is upregulated, whereas CBS is downregulated in GC tissues compared to matched normal tissues; and GC patients with high /low CBS levels have a worse clinical outcome and a poorer response to chemotherapy.

CONCLUSION

Our study reveals a novel mechanism in how HIF1α/ modulates ferroptosis/chemoresistance in GC, illuminating potential therapeutic targets for refractory hypoxic tumors.