GSK-J4 Suppresses Tumorigenesis by Targeting the PERK-c-Myc Pathway Through Endoplasmic Reticulum Stress Activation...

The limited and inconsistent efficacy of existing therapies for tuberous sclerosis complex (TSC) has driven the exploration of novel strategies, including epigenetic regulation. GSK-J4, an inducer of global H3K27me3 accumulation, shows broad anti-tumor activity. However, its therapeutic potential in TSC remains unclear. In the study, we reported that GSK-J4 inhibited cell cycle progression and induced apoptosis in primary Tsc1^+/- and Tsc2^+/- MEFs. Mechanistically, Tsc1 or Tsc2 deletion reduced global H3K27me3, correlating with increased viability, accelerated cell cycle, and suppressed apoptosis-phenotypes reversed by GSK-J4. Moreover, GSK-J4 triggered endoplasmic reticulum stress (ERS) by activating the PERK-ATF4-CHOP axis, which concurrently downregulated the proto-oncogene c-Myc, outlining a GSK-J4→p-PERK→c-Myc inhibitory pathway. Notably, GSK-J4 synergized with rapamycin to enhance cell cycle arrest and apoptosis. In vivo, this combination alleviated renal impairment in Tsc1- or Tsc2-deficient models, suggesting a promising therapeutic strategy for TSC patients with suboptimal response to mammalian target of rapamycin complex 1 (mTORC1) inhibitors. Our study elucidates a specific ERS-dependent anti-tumor mechanism of GSK-J4 in Tsc-deficient contexts and demonstrates the synergistic efficacy of combining epigenetic and mTORC1 inhibitors.