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ATM-dependent activation of SIM2s regulates homologous recombination and epithelial–mesenchymal transition

Oncogene volume 38, pages 2611–2626 (2019)Cite this article

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Abstract

There is increasing evidence that genomic instability is a prerequisite for cancer progression. Here we show that SIM2s, a member of the bHLH/PAS family of transcription factors, regulates DNA damage repair through enhancement of homologous recombination (HR), and prevents epithelial–mesenchymal transitions (EMT) in an Ataxia-telangiectasia mutated (ATM)-dependent manner. Mechanistically, we found that SIM2s interacts with ATM and is stabilized through ATM-dependent phosphorylation in response to IR. Once stabilized, SIM2s interacts with BRCA1 and supports RAD51 recruitment to the site of DNA damage. Loss of SIM2s through the introduction of shSIM2 or the mutation of SIM2s at one of the predicted ATM phosphorylation sites (S115) reduces HR efficiency through disruption of RAD51 recruitment, resulting in genomic instability and induction of EMT. The EMT induced by the mutation of S115 is characterized by a decrease in E-cadherin and an induction of the basal marker, K14, resulting in increased invasion and metastasis. Together, these results identify a novel player in the DNA damage repair pathway and provides a link in ductal carcinoma in situ progression to invasive ductal carcinoma through loss of SIM2s, increased genomic instability, EMT, and metastasis.

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Acknowledgements

We thank the Histology Core Facility at Texas A&M University College of Veterinary Medicine & Biomedical Sciences for tissue preparation and H&E staining and the University of Kansas Medical Center for providing the human samples, tissue microarray, and pathology information. Confocal microscopy was performed in the Texas A&M University College of Veterinary Medicine & Biomedical Sciences Image Analysis Laboratory, supported by NIH-NCRR (1S10RR22532–01) grant. We acknowledge support from the University of Kansas (KU) Cancer Center’s Biospecimen Repository Core Facility staff for helping obtain human specimens. We also acknowledge support from the KU Cancer Center’s Cancer Center Support Grant (P30 CA168524).

Funding

National Cancer Institute R21CA190941 (WP); R01HD083952 (CO-PI WP, MR); R21CA185460 (FB) Department of Defense (DOD-CDMRP) W81XWH-11–1–0158 (KCS) American Association for Cancer Research (AACR)—2014 Breast Cancer Research Foundation—Translational Breast Cancer research (FB)

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  1. Weston W. Porter

    Present address: Veterinary Integrative Biosciences, Texas A&M University, College of Veterinary Medicine, College Station, TX, 77843, USA

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  1. Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA

    Scott J. Pearson, Tapasree Roy Sarkar, Cole M. McQueen, Jessica Elswood, Emily E. Schmitt, Steven W. Wall, Kelly C. Scribner, Garhett Wyatt, Rola Barhoumi, Monique Rijnkels & Weston W. Porter

  2. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Fariba Behbod

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Pearson, S.J., Roy Sarkar, T., McQueen, C.M. et al. ATM-dependent activation of SIM2s regulates homologous recombination and epithelial–mesenchymal transition. Oncogene 38, 2611–2626 (2019). https://doi.org/10.1038/s41388-018-0622-4

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