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

  • J Adv Res. 2021 Oct 5:37:91-106. doi: 10.1016/j.jare.2021.10.001.
Hui Yang  1  2 ,  Yiren Hu  1  3 ,  Mingzhe Weng  1  4 ,  Xiaocen Liu  1  5 ,  Ping Wan  1  6 ,  Ye Hu  7 ,  Mingzhe Ma  1  8  9 ,  Yan Zhang  1  10 ,  Hongping Xia  11 ,  Kun Lv  1  2
Affiliations
  • 1. Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), Wuhu, Anhui 241001, China.
  • 2. Central Laboratory, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, China.
  • 3. Department of General Surgery, Wenzhou No.3 Clinical Institute of Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, Zhejiang 325000, China.
  • 4. Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200032, China.
  • 5. Department of Nuclear Medicine, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, China.
  • 6. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200032, China.
  • 7. State Key Laboratory for Oncogenes and Related Genes; Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
  • 8. Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
  • 9. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 10. Department of Gastroenterology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, PR China.
  • 11. Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 169610, Singapore.
PMID: 35499052 DOI: 10.1016/j.jare.2021.10.001
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.

Keywords
4-HNE, 4-hydroxynonenal; AJCC, American Joint Committee on Cancer; CDS, coding sequence; CHIP, chromatin immunoprecipitation; Chemoresistance; DZNeP, 3-deazaneplanocin A; FBS, fetal bovine serum; Ferroptosis; GC, gastric cancer; GEO, Gene Expression Omnibus; Gastric cancer; HE, Hematoxylin and eosin; HREs, hypoxia response elements; Hypoxia; IHC, immunohistochemical; MDA, malondialdehyde; RIP, RNA immunoprecipitation; TCGA, the cancer genome atlas; TNM, tumor-node-metastasis staging system; YTHDF2, YTH domain family protein 2; lncRNA; lncRNA, long noncoding RNA; qPCR, quantitative real-time PCR.
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