Abstract 3839: MIG-6 plays as a tumor suppressor to inhibit angiogenesis by downregulating HDAC1 in PTEN-deficient endometrial cancer

Abstract Endometrioid endometrial cancer (EEC) is the most prevalent gynecological malignancy. Metastatic and recurrent endometrial cancer is incurable with currently available standard therapies. While Mig-6 mutation develops distant metastasis and recurrence of EEC with Pten deficiency, Mig-6 overexpression (Ptend/dMig-6over mice) suppresses tumor development. Therefore, there is an urgent need to explore the mechanisms of tumor metastasis and recurrence to further elucidate the progression of EEC. We performed RNA-seq analysis to identify targets of Mig-6 in Ptend/d and Ptend/dMig-6over mice. The transcriptomic analysis identified 104 and 518 genes significantly increased or decreased transcripts in Ptend/dMig-6over mice compared to Ptend/d mice. The pathway analysis of these dysregulated genes showed significant inhibition of immune, inflammatory, and angiogenesis pathways in Ptend/dMig-6over compared to the Ptend/d mice group, where the key regulator was hypoxia-inducible factor-1 (HIF1A). Immunohistochemical analysis of HIF1A and PECAM1 validated a significant reduction of angiogenesis in Ptend/dMig-6over mice. Moreover, combined interactome and immunoprecipitation analyses revealed that MIG-6 directly binds with histone deacetylase 1 (HDAC1) in the EEC of Ptend/dMig-6over mice. Our double immunofluorescence results confirmed colocalization of two proteins in EEC. Finally, we evaluated the therapeutic effect of Panobinostat, a HDAC inhibitor, in EEC of Ptend/d mice. Our results demonstrate the tumor suppressor role of MIG-6 as an HDAC1 interacting protein in angiogenesis of EEC. Our findings highlight potential molecular targets of EEC that could significantly enhance therapeutic strategies for endometrial cancer. Citation Format: Shamsun Nahar, Jiyoung Yu, Haeam Lee, Rong Li, Jin-Seok Jung, Tae Hoon Kim, Kyunggon Kim, Jung-Yoon Yoo, Jae-Wook Jeong. MIG-6 plays as a tumor suppressor to inhibit angiogenesis by downregulating HDAC1 in PTEN-deficient endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3839.