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.