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<p>Gastric cancer (GC) continues to be a major contributor to global cancer mortality, underscoring the need to elucidate its molecular mechanisms to develop effective therapies. Cuproptosis, a copper-dependent form of cell death, exhibits tumor-suppressive effects in GC. Clinical specimens revealed elevated expression of solute carrier family 39 member 4 (SLC39A4) in GC tissues, correlating with poor prognosis. However, the role of SLC39A4 in GC remains unclear. Using lentiviral transduction in AGS and MKN-45 cell lines, we established stable monoclonal strains with SLC39A4 overexpression and knockdown for functional studies. SLC39A4 promotes GC cell proliferation both in vitro and in vivo. CuCl<sub>2</sub> and elesclomol treatment induced cuproptosis, which was attenuated by SLC39A4 overexpression but potentiated by SLC39A4 knockdown, as confirmed through proliferation assays and cuproptosis marker analyses in cell cultures and xenograft models. Mechanistically, the m6A reader protein YTHDF1, frequently overexpressed in GC patients and known to inhibit elesclomol-induced cuproptosis, bound to SLC39A4 mRNA and stabilized its transcripts. Dual-luciferase assays demonstrated that mutation of the m6A site within SLC39A4’s coding sequence abolished YTHDF1-mediated regulation. These findings establish SLC39A4 as a promoter of GC progression through cuproptosis suppression, modulated by YTHDF1 <i>via</i> m6A-dependent mRNA stabilization, revealing potential therapeutic targets for GC treatment.</p><p></p>

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YTHDF1/SLC39A4 signaling axis promotes gastric cancer cell proliferation by suppressing cuproptosis ex vivo and in vitro

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Jingying Su,
  • Jihan Qi,
  • Binhua Xu,
  • Jiaxin Wang,
  • Ram Prasad Chaulagain,
  • Hongliang Chen,
  • Ning Li,
  • Xinyu Jiang,
  • Lingyi Xu,
  • Fengchun Li,
  • Wenli Mao,
  • Shizhu Jin

摘要

Gastric cancer (GC) continues to be a major contributor to global cancer mortality, underscoring the need to elucidate its molecular mechanisms to develop effective therapies. Cuproptosis, a copper-dependent form of cell death, exhibits tumor-suppressive effects in GC. Clinical specimens revealed elevated expression of solute carrier family 39 member 4 (SLC39A4) in GC tissues, correlating with poor prognosis. However, the role of SLC39A4 in GC remains unclear. Using lentiviral transduction in AGS and MKN-45 cell lines, we established stable monoclonal strains with SLC39A4 overexpression and knockdown for functional studies. SLC39A4 promotes GC cell proliferation both in vitro and in vivo. CuCl2 and elesclomol treatment induced cuproptosis, which was attenuated by SLC39A4 overexpression but potentiated by SLC39A4 knockdown, as confirmed through proliferation assays and cuproptosis marker analyses in cell cultures and xenograft models. Mechanistically, the m6A reader protein YTHDF1, frequently overexpressed in GC patients and known to inhibit elesclomol-induced cuproptosis, bound to SLC39A4 mRNA and stabilized its transcripts. Dual-luciferase assays demonstrated that mutation of the m6A site within SLC39A4’s coding sequence abolished YTHDF1-mediated regulation. These findings establish SLC39A4 as a promoter of GC progression through cuproptosis suppression, modulated by YTHDF1 via m6A-dependent mRNA stabilization, revealing potential therapeutic targets for GC treatment.