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 Shimberg, Michele I. Vitolo, Stuart S. Martin, Denis Wirtz, Ronny Drapkin, Jianhua Xuan, Tian Li Wang, Ie Ming Shih

Research output: Contribution to journalArticle

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 ARID1AWT and ARID1AKO 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.

Original languageEnglish (US)
Article number2717
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Suryo Rahmanto, Y., Shen, W., Shi, X., Chen, X., Yu, Y., Yu, Z. C., Miyamoto, T., Lee, M. H., Singh, V., Asaka, R., Shimberg, G., Vitolo, M. I., Martin, S. S., Wirtz, D., Drapkin, R., Xuan, J., Wang, T. L., & Shih, I. M. (2020). Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming. Nature communications, 11(1), [2717]. https://doi.org/10.1038/s41467-020-16416-0