Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming
Yohan Suryo Rahmanto, Wenjing Shen, Xu Shi, Xi Chen, Yu Yu, Zheng-Cheng Yu, Tsutomu Miyamoto, Meng-Horng Lee, Vivek Singh, Ryoichi Asaka, Geoffrey D. Shimberg, Michele Vítolo, Stuart S. Martin, Denis Wirtz, Ronny Drapkin, Jianhua Xuan, Tian‐Li Wang, Ie‐Ming Shih
Abstract
Abstract Somatic inactivating mutations of ARID1A , a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1A WT and ARID1A KO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A -deficiency lead to loss of TGF-β tumor suppressive function and that inactivation of ARID1A/TGF-β axis promotes migration and invasion of PTEN -deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.