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<p>c-Myc is broadly hyperactivated in colon cancer, yet the mechanisms sustaining its transcriptional activation remain elusive. Here we identify palmitic acid (PA) as a metabolite cue that activates c-Myc via dual palmitoylation-dependent pathways operating across tumor initiation and progression. In colitis models, PA-rich diets exacerbate inflammation and enrich MYC target programs without increasing <i>Myc</i> mRNA. Mechanistically, the palmitoyltransferase ZDHHC9, upregulated by IL-1β, directly palmitoylates c-Myc at C171, enhancing c-Myc/MAX dimerization and transcriptional activity; genetic or pharmacologic inhibition diminishes c-Myc palmitoylation and target gene expression. During tumor progression, c-Myc transactivates FATP2, increasing PA uptake and reinforcing c-Myc palmitoylation, thereby establishing a feedforward loop and metabolic addiction to PA. Functionally, PA accelerates xenograft growth, whereas targeting ZDHHC9 and FATP2 inhibits c-Myc function to suppress tumor burden. These findings uncover metabolite-driven control of c-Myc through palmitoylation and highlight ZDHHC9/FATP2 as actionable vulnerabilities for colon cancer treatment.</p>

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Palmitic acid activates c-Myc via dual palmitoylation-dependent pathways to promote colon cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月17日

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  • Wenxin Du,
  • Jianing Zhang,
  • Yuexin Wang,
  • Minjun Li,
  • Ji Cao,
  • Bo Yang,
  • Qiaojun He,
  • Xuejing Shao,
  • Meidan Ying

摘要

c-Myc is broadly hyperactivated in colon cancer, yet the mechanisms sustaining its transcriptional activation remain elusive. Here we identify palmitic acid (PA) as a metabolite cue that activates c-Myc via dual palmitoylation-dependent pathways operating across tumor initiation and progression. In colitis models, PA-rich diets exacerbate inflammation and enrich MYC target programs without increasing Myc mRNA. Mechanistically, the palmitoyltransferase ZDHHC9, upregulated by IL-1β, directly palmitoylates c-Myc at C171, enhancing c-Myc/MAX dimerization and transcriptional activity; genetic or pharmacologic inhibition diminishes c-Myc palmitoylation and target gene expression. During tumor progression, c-Myc transactivates FATP2, increasing PA uptake and reinforcing c-Myc palmitoylation, thereby establishing a feedforward loop and metabolic addiction to PA. Functionally, PA accelerates xenograft growth, whereas targeting ZDHHC9 and FATP2 inhibits c-Myc function to suppress tumor burden. These findings uncover metabolite-driven control of c-Myc through palmitoylation and highlight ZDHHC9/FATP2 as actionable vulnerabilities for colon cancer treatment.