1. The hypoxic microenvironment is a common hallmark of solid tumors and is strongly associated with therapy resistance and poor prognosis.
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2. CBSLR, a long noncoding RNA transactivated by HIF-1α, is upregulated in GC and associated with poor prognosis.
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3. CBSLR inhibition induces ferroptosis under hypoxic conditions and contributes to chemoresistance.
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4. lncRNA-CBSLR recruits YTHDF2 protein and CBS mRNA to form CBSLR/ YTHDF2/CBS complex, which in turn decreases CBS mRNA stability in an m6A dependent manner.
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5. CBSLR/CBS inhibits ferroptosis by modulating ACSL4 methylation to be polyubiquitinated.
Abstract
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.
Graphical abstract
Schematic diagram showing that HIF-1α induces lncRNA-CBSLR to recruit YTHDF2 protein and CBS mRNA to form CBSLR/ YTHDF2/CBS complex, which in turn decreases CBS mRNA stability in an m6A dependent manner. The decreased CBS expression reduced methylation of ACSL4 protein, thus, the protein is degraded via the ubiquitination-proteasome pathway. It eventually protects GC from ferroptosis under a hypoxic tumor microenvironment.
