Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming

• Published in: Nature communications Vol. 11; no. 1; pp. 2717 - 14
• Main Authors: Suryo Rahmanto, Yohan, Shen, Wenjing, Shi, Xu, Chen, Xi, Yu, Yu, Yu, Zheng-Cheng, Miyamoto, Tsutomu, Lee, Meng-Horng, Singh, Vivek, Asaka, Ryoichi, Shimberg, Geoffrey, Vitolo, Michele I., Martin, Stuart S., Wirtz, Denis, Drapkin, Ronny, Xuan, Jianhua, Wang, Tian-Li, Shih, Ie-Ming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14/1; 45/15; 45/91; 631/208; 631/67; 631/80; 64/110; 692/420; Animal models; Animals; Cancer; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinoma; Carcinoma, Endometrioid - genetics; Carcinoma, Endometrioid - metabolism; Carcinoma, Endometrioid - pathology; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells, Cultured; Cellular Reprogramming - genetics; Chromatin remodeling; Deactivation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Endometrium; Endometrium - cytology; Endometrium - metabolism; Epithelial cells; Female; Gene Expression Profiling - methods; Genetic engineering; Humanities and Social Sciences; Humans; Inactivation; Mice, 129 Strain; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; multidisciplinary; Mutation; PTEN protein; Science; Science (multidisciplinary); Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor cells; Tumorigenesis; Tumors; Uterus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16416-0

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.
ARID1A, which is often mutated in human endometrial cancer, is a component of the SWI/SNF chromatin remodelling complex. Here, the authors show that
Arid1a
mutations in the mouse endometrium and primary human endometrial epithelial cells cause widespread reprogramming of gene transcription and result in a loss of response to TGFβ.