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 m6Amodified 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 down regulated 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 HIF1a/CBSLR modulates ferroptosis/chemoresistance in GC, illuminating potential therapeutic targets for refractory hypoxic tumors.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
[1]Wannan Med Coll, Key Lab Noncoding RNA Transformat Res Anhui Highe, Wuhu 241001, Anhui, Peoples R China.
[2]Wannan Med Coll, Affiliated Hosp 1, Cent Lab, Yijishan Hosp, Wuhu 241001, Anhui, Peoples R China.
[3]Wenzhou Med Univ, Wenzhou Peoples Hosp, Dept Gen Surg, Wenzhou 3 Clin Inst, Wenzhou 325000, Zhejiang, Peoples R China.
[4]Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gen Surg, Shanghai 200032, Peoples R China.
[5]Wannan Med Coll, Yijishan Hosp, Dept Nucl Med, Affiliated Hosp 1, Wuhu 241001, Anhui, Peoples R China.
[6]Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Liver Surg, Shanghai 200032, Peoples R China.
[7]Shanghai Jiao Tong Univ, Ren Ji Hosp, State Key Lab Oncogenes & Related Genes, Sch Med, Shanghai 200032, Peoples R China.
[8]Shanghai Jiao Tong Univ, Ren Ji Hosp, Div Gastroenterol & Hepatol, Sch Med, Shanghai 200032, Peoples R China.
[9]Fudan Univ, Dept Gastr Surg, Shanghai Canc Ctr, Shanghai 200032, Peoples R China.
[10]Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China.
[11]Wannan Med Coll, Yijishan Hosp, Dept Gastroenterol, Affiliated Hosp 1, Wuhu 241001, Anhui, Peoples R China.
[12]Natl Canc Ctr Singapore, Div Cellular & Mol Res, Lab Canc Genom, Singapore 169610, Singapore.
(8.0+极速模式)