Targeting hypoxia-induced CBS expression inhibits breast cancer stem cells through the induction of ferroptosis.
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ABSTRACT:
SUBMITTER: Wei G
PROVIDER: S-EPMC10405013 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
Publications
Targeting hypoxia-induced CBS expression inhibits breast cancer stem cells through the induction of ferroptosis.
Wei Guangyao G Liu Jia J Lan Jie J Ji Guangyu G Xia Huize H Zhao Zhiqun Z Yu Zhaoxue Z Sun Rong R Zhang Chuanzhao C Lu Haiquan H
Genes & diseases 20230328 6
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Project description:IntroductionTumors are usually refractory to anti-cancer therapeutics under hypoxic conditions. However, the underlying molecular mechanism remains to be elucidated.ObjectivesOur study intended to identify hypoxia inducible lncRNAs and their biological function in gastric cancer (GC).MethodsDifferentially 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.ResultsWe 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.ConclusionOur study reveals a novel mechanism in how HIF1α/CBSLR modulates ferroptosis/chemoresistance in GC, illuminating potential therapeutic targets for refractory hypoxic tumors.
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