GSDME acts as an epigenetic modifier to promote melanoma development via centriole biogenesis regulator PLK4

  • Cell Death Differ. 2026 May 25. doi: 10.1038/s41418-026-01767-w.
Juan Du  #  1 ,  Yuqi Yang  #  1 ,  Mao Zhao  #  1 ,  Hengxiang Zhang  #  1 ,  Xia Li  1 ,  Di Qu  1 ,  Jianzhang Wang  2 ,  Xiangxu Wang  3 ,  Xiuli Yi  1 ,  Jingjing Ma  1 ,  Huina Wang  1 ,  Hao Wang  1 ,  Qiong Shi  1 ,  Yangzi Tian  1 ,  Baolu Zhang  1 ,  Sen Guo  1 ,  Tianwen Gao  1 ,  Weinan Guo  4  5  6 ,  Chunying Li  7
Affiliations
  • 1. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 2. Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 3. Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 4. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. [email protected].
  • 5. Innovation Research Institute, Xijing Hospital, Fourth Military Medical University, Xi'an, China. [email protected].
  • 6. Military Medical Innovation Center, Fourth Military Medical University, Xi'an, China. [email protected].
  • 7. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. [email protected].
  • # Contributed equally.
PMID: 42185629 DOI: 10.1038/s41418-026-01767-w
Abstract

Gasdermins have been traditionally recognized for their canonical pore-forming activity in Pyroptosis and generally considered as a tumor suppressor due to their low endogenous expression in various types of cancers. However, the pyroptosis-independent role of gasdermins in cellular biological processes remains poorly understood, sparking debates on their actual contribution to Cancer pathogenesis. Here, we demonstrate a novel facet of GSDME as an epigenetic modifier that promotes melanoma development through the regulation of the centriole biogenesis regulator PLK4. Unexpectedly, GSDME expression is significantly up-regulated in melanoma, induced by prominent hypo-methylation at its promoter. The deficiency of GSDME prominently suppresses tumor growth and metastasis of melanoma, independent of CD8+ T cell-dependent anti-tumor immunity. Mechanistically, GSDME forms a complex with SMARCA5 and NCL in the nucleus, functioning as an epigenetic regulator, particularly facilitating the transcription of centriole biogenesis regulator PLK4 by increasing its promoter chromatin accessibility. The regulation of PLK4 is greatly implicated in the oncogenic role of GSDME in melanoma. Ultimately, this GSDME-SMARCA5/NCL-PLK4 axis is validated in patients with melanoma and has been proved of promising prognostic potential. Altogether, these results demonstrate that GSDME could be a critical oncogene through its pyroptosis-independent epigenetic regulatory function.

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