POU6F1 promotes ferroptosis by increasing lncRNA-CASC2 transcription to regulate SOCS2/SLC7A11 signaling in gastric cancer

Cell Biol Toxicol. 2024 Jan 25;40(1):3. doi: 10.1007/s10565-024-09843-y.

Abstract

Objective: This study investigated the effect and mechanism of POU6F1 and lncRNA-CASC2 on ferroptosis of gastric cancer (GC) cells.

Methods: GC cells treated with erastin and RSL3 were detected for ferroptosis, reactive oxygen species (ROS) level, and cell viability. The expression levels of POU6F1, lncRNA-CASC2, SOCS2, and ferroptosis-related molecules (GPX4 and SLC7A11) were also measured. The regulations among POU6F1, lncRNA-CASC2, FMR1, SOCS2, and SLC7A11 were determined. Subcutaneous tumor models were established, in which the expressions of Ki-67, SOCS2, and GPX4 were detected by immunohistochemistry.

Results: GC patients with decreased expressions of POU6F1 and lncRNA-CASC2 had lower survival rate. Overexpression of POU6F1 or lncRNA-CASC2 decreased cell proliferation and GSH levels in GC cells, in addition to increasing total iron, Fe2+, MDA, and ROS levels. POU6F1 directly binds to the lncRNA-CASC2 promoter to promote its transcription. LncRNA-CASC2 can target FMR1 and increase SOCS2 mRNA stability to promote SLC7A11 ubiquitination degradation and activate ferroptosis signaling. Knockdown of SOCS2 inhibited the ferroptosis sensitivity of GC cells and reversed the effects of POU6F1 and lncRNA-CASC2 overexpression on ferroptosis in GC cells.

Conclusion: Transcription factor POU6F1 binds directly to the lncRNA-CASC2 promoter to promote its expression, while upregulated lncRNA-CASC2 increases SOCS2 stability and expression by targeting FMR1, thereby inhibiting SLC7A11 signaling to promote ferroptosis in GC cells and inhibit GC progression.

Keywords: Ferroptosis; Gastric cancer; LncRNA-CASC2; SOCS2; Transcription factor POU6F1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / genetics
  • Ferroptosis*
  • Fragile X Mental Retardation Protein
  • Humans
  • POU Domain Factors
  • RNA, Long Noncoding* / genetics
  • Reactive Oxygen Species
  • Signal Transduction
  • Stomach Neoplasms* / genetics
  • Suppressor of Cytokine Signaling Proteins

Substances

  • Amino Acid Transport System y+
  • FMR1 protein, human
  • Fragile X Mental Retardation Protein
  • POU Domain Factors
  • POU6F1 protein, human
  • Reactive Oxygen Species
  • RNA, Long Noncoding
  • SLC7A11 protein, human
  • SOCS2 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • long non-coding RNA CASC2, human