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ARID1A and CEBPα cooperatively inhibit UCA1 transcription in breast cancer

Oncogene volume 37, pages 5939–5951 (2018)Cite this article

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Abstract

As one of the primary members of SWI/SNF chromatin remodeling complexes, ARID1A contains frequent loss-of-function mutations in many types of cancers. However, the molecular mechanisms underlying ARID1A deficiency in cancer biology remain to be investigated. Using breast cancer as a model, we report that silencing ARID1A significantly increased cellular proliferation and migration. Mechanistically, primarily functioning as a transcriptional repressor, loss of ARID1A profoundly alters histone modifications and the transcriptome. Notably, ARID1A inhibited the expression of a long non-coding RNA, UCA1, by regulating chromatin access of the transcription factor CEBPα. Restoration experiments showed that UCA1 mediates the functions of ARID1A that induces loss of cellular proliferation and migration. Together, our findings characterize ARID1A as a key tumor-suppressor gene in breast cancer through cooperation with CEBPα, and loss-of-function mutations of ARID1A activates UCA1.

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Acknowledgements

ARID1A shRNA and ARID1A CRISPR-Cas9 plasmid are gifts from Vikas Madan, Cancer Science Institute of Singapore; pCDH-CMV-UCA1-EF1-copGFP is a gift from Yin-Yuan Mo, University of Mississippi Medical Center. This research was supported by the National Research Foundation Singapore under its Singapore Translational Research Investigator Award (NMRC/STaR/0021/2014) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), the NMRC Centre Grant awarded to National University Cancer Institute, the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Centers of Excellence initiatives to H.P.K. This study was additionally funded by the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s Tier 3 grants (MOE2014-T3-1-006). D.-C.L was supported by Tower Cancer Research Foundation. Part research was supported by National Natural Science Foundation of China (NSFC, 31401594, to X.G.) and the generous support of Michele and Ted Kaplan Family Fund and the Tower Foundation.

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Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Xiao Guo, Yin Zhang, Le-Hang Lin & Dong Yin

  2. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Xiao Guo, Saadiya Zia, Sigal Gery, De-Chen Lin & H. Phillip Koeffler

  3. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Anand Mayakonda, Vikas Madan, Ling-Wen Ding & H. Phillip Koeffler

  4. Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA

    Jeffrey W. Tyner

  5. Department of Medicine, College of Medicine and Health, Lishui University, Zhejiang, China

    Wu Zhou

  6. National University Cancer Institute, National University Hospital, Singapore, Singapore

    H. Phillip Koeffler

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  1. Xiao Guo
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Guo, X., Zhang, Y., Mayakonda, A. et al. ARID1A and CEBPα cooperatively inhibit UCA1 transcription in breast cancer. Oncogene 37, 5939–5951 (2018). https://doi.org/10.1038/s41388-018-0371-4

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