NSD1-Mediated PPARγ Methylation Enhances PTEN Activity to Suppress Glycolysis and Tumor Progression in Endometrial Cancer

Metabolic reprogramming is a defining feature of endometrial cancer. The upstream molecular mechanisms driving altered metabolism in endometrial cancer represent potential therapeutic targets. In this study, we identified the lysine methyltransferase NSD1-frequently mutated in endometrial cancer-as a key epigenetic regulator of tumor metabolism. NSD1 directly monomethylated PPARγ at lysine 98 (K98), which enhanced the nuclear localization of PPARγ and promoted transcriptional activation of the tumor suppressor gene PTEN. The resulting elevated PTEN levels led to reduced glycolytic metabolism, cellular proliferation, and invasive potential in endometrial cancer cells. Loss-of-function mutations in NSD1 abolished PPARγ K98 methylation, resulting in its cytoplasmic retention and impaired PTEN transcription. The consequent depletion of PTEN amplified glycolysis and drove tumor progression. Remarkably, restoration of PTEN expression or pharmacologic inhibition of AKT effectively reversed the heightened glycolytic activity and malignant phenotype associated with NSD1 deficiency. Together, these findings reveal a critical epigenetic-metabolic axis in endometrial cancer, in which NSD1-mediated methylation of PPARγ at K98 orchestrates tumor-suppressive metabolic control via PTEN. These insights not only elucidate a regulatory pathway in endometrial cancer pathogenesis but also highlight potential therapeutic targets for intervention in metabolically driven tumors. Significance: Methylation of PPARγ by NSD1 promotes PTEN expression to block glycolytic metabolism reprogramming in endometrial cancer, revealing a targetable vulnerability in NSD1-deficient tumors.