2026/07/13 by Meng-Yen Li, Aubrey E. Houser, Pradeep Singh Cheema +12 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cancer Cells and Metastasis #Epigenetics and DNA Methylation #Histone Deacetylase Inhibitors Research
paper · doi:10.1038/s41467-026-75529-0
openalex publication_date 2026/07/13 · openalex created_date 2026/07/14 · openalex updated_date 2026/07/27
Squamous cell carcinomas (SCCs) are common epithelial malignancies frequently associated with EZH2 upregulation, which correlates with aggressive growth and poor prognosis. EZH2 functions as the catalytic subunit of Polycomb repressive complex 2 (PRC2), which deposits the repressive H3K27me3 histone mark, yet PRC2 function in SCC pathogenesis remains unresolved. Here, we uncover a paradox: although EZH2 is elevated, the PRC2-catalyzed H3K27me3 is profoundly reduced in human SCC and complementary murine models. Mechanistically, we identify that oncogenic Ras signaling causes degradation of the PRC2 subunit EED, destabilizing PRC2 and depleting H3K27me3. Loss of EED reprograms keratinocytes into an aggressive tumor-specific cell state and induces paracrine factors that remodel the tumor microenvironment, driving metastasis. Remarkably, reintroducing EED suppresses tumor growth via restoring PRC2 integrity and H3K27me3 levels, revealing the reversibility of this epigenetic collapse. These findings link oncogenic signaling to epigenetic reprogramming and uncover PRC2 reconstitution as a potential therapeutic option in epithelial cancers. Oncogenic Ras signaling is linked to aggressive squamous cell carcinoma (SSC). Here, authors show that Ras signaling leads to proteasomal degradation of EED, resulting in reduced H3K27me3 and activation of oncogenic transcriptional programs in SCC.