MIG-6 Regulates HDAC1-Mediated Angiogenesis and Tumorigenesis in PTEN-Deficient Endometrioid Endometrial Cancer
Abstract
Endometrioid endometrial cancer (EEC) is the most prevalent gynecologic malignancy, yet no targeted therapies are currently approved by the FDA specifically for it. To identify therapeutic targets for EEC, we performed transcriptomic and proteomic analyses in genetically engineered preclinical cancer models, including uterine-specific phosphatase and tensin homolog (Pten)-deficient (Ptend/d) mice and Ptend/d mice with additional overexpression of the tumor suppressor mitogen-inducible gene 6 (Mig-6) that develop EEC. Transcriptomic analysis revealed significant inhibition of immune, inflammatory, and angiogenesis pathways, with hypoxia-inducible factor-1α (HIF1α) as a key upstream regulator. Interactome and immunoprecipitation analyses identified HDAC1 as a MIG-6–interacting protein that mediates angiogenic signaling in PTEN-deficient endometrial cancer. MIG-6 overexpression suppressed HDAC1 activity and downstream HIF1α-driven angiogenesis. Pharmacologic inhibition of HDAC1 with panobinostat recapitulated the tumor-suppressive effects observed with MIG-6 overexpression. These findings suggest that HDAC1 may represent a potential therapeutic target in EEC and that HDAC inhibition can attenuate early tumor progression and angiogenic signaling in preclinical models.
Implications:
This study identifies the MIG-6–HDAC1 axis as a key regulator of angiogenesis in EEC, highlighting HDAC1 inhibition as a promising targeted therapeutic strategy for early tumor suppression.
