PER2 suppresses glioma progression through physical association with KRAS and attenuation of PI3K-AKT-mTOR pathway activation

Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis. The circadian gene PER2 has been reported to exhibit tumor-suppressive functions, while KRAS is a key oncogenic driver. This study aims to investigate the mechanistic interaction between PER2 and KRAS in gliomagenesis. PER2 expression was analyzed using TCGA data and human GBM samples. A spontaneous glioma mouse model (GK, GFAP-Cre ⁺/⁻ KRAS ⁺/⁻ ) was generated for RNA‑seq. PER2 knockout in this model (GKP, GFAP-Cre ⁺/⁻ KRAS ⁺/⁻ PER2 flox/flox ) was used to assess survival, histopathology, and proliferation/apoptosis. In vitro, primary astrocytes with KRAS overexpression (KOE) and KRAS/PER2 co‑overexpression (KPOE) were established. Physical association between PER2 and KRAS was assessed by co‑IP. Cell proliferation, migration, invasion, cycle, and apoptosis were evaluated. PI3K‑AKT‑mTOR pathway activation was determined by Western blot. PER2 was downregulated in human GBM and correlated with poor prognosis. In GK mice, PER2 was a downregulated circadian gene, concurrent with MAPK/RAS pathway activation. PER2 knockout (GKP) accelerated tumor progression, shortened survival, increased proliferation (Ki67, p‑Histone H3), and reduced apoptosis (TUNEL). Co‑IP revealed a physical association between PER2 and KRAS. PER2 co‑expression reversed KRAS‑driven increases in migration, invasion, and proliferation. Mechanistically, KRAS activated the PI3K‑AKT‑mTOR pathway, which was attenuated by PER2 co‑expression. PER2 co‑expression was also associated with G0/G1 arrest and increased apoptosis, accompanied by modulation of the BAX/BCL‑2 ratio. Collectively, PER2 physically associates with KRAS and attenuates KRAS‑driven activation of the PI3K‑AKT‑mTOR pathway, correlating with cell cycle arrest and apoptosis. Together, these findings suggest the PER2‑KRAS axis as a potential therapeutic target in glioma.