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LRH1 enhances cell resistance to chemotherapy by transcriptionally activating MDC1 expression and attenuating DNA damage in human breast cancer

Oncogene volume 37, pages 3243–3259 (2018)Cite this article

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Abstract

Liver receptor homolog-1 (LRH1) has been shown to promote tumor proliferation and development. However, the functions of LRH1 in mediating cancer cells chemoresistance are still not clear. Here, we found LRH1 levels were significantly elevated in primary breast cancer tissues in patients who developed early recurrence. Similarly, adriamycin (ADR)-resistant breast cancer cell lines also exerted high LRH1 expression. Indeed, overexpression of LRH1 attenuated cytotoxicity of chemotherapeutic drugs ADR and cisplatin (DDP) in breast cancer cells in vitro and in nude mice tumor model. Comet and BrdU assays showed overexpression of LRH1 blocked breast cancer cells DNA damage by chemotherapeutic drug, whereas depletion of LRH1 enhanced DNA damage. Remarkably, knockdown of LRH1 decreased the levels and foci of DNA damage marker γH2AX induced by ADR and DDP. Furthermore, plasmid end-joining assay indicated that knockdown of LRH1 significantly decreased non-homologous end-joining (NHEJ)-mediated double-strand break (DSB) repair efficiencies. Afterwards, we provided evidences that LRH1 promoted MDC1 transcription by directly activating MDC1 promoter and therefore increased γH2AX levels. Importantly, a LRH1-binding site mapped between −1812 and −1804 bp of the proximal MDC1 promoter was identified. Moreover, LRH1 and MDC1 mRNA levels were positively correlated in recurrent breast cancer samples. These results implied LRH1 enhanced breast cancer cell chemoresistance by upregulating MDC1 and attenuating DNA damage. Additionally, we elucidated the coactivator NCOA3 acted synergistically with LRH1 to promote MDC1 expression and chemoresistance. Altogether, LRH1-MDC1 signaling might be considered as a novel molecular target for designing novel therapeutic regimen in chemotherapy resistance breast cancer.

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Acknowledgements

We are grateful to Dr. Simak Ali (Imperial College London, London) for providing pCI-HA3-LRH1 plasmid, to Dr. Michal Goldberg (Hebrew University of Jerusalem, Jerusalem) for providing HA-MDC1 plasmid, to Dr. Vera Gorbunova for providing the pEGFP-Pem1-Ad2 plasmid, to Prof. B-A Li (Xiamen University) for providing the MDA-MB-231/ADR and T47D/ADR cells. This study was supported by grants from the National Natural Science Foundation of China (No. 81772803, 81630046, 81402187); Ph.D. Start-Up Fund of Natural Science Foundation of Guangdong Province (No. 2014A030310505 to ZZ); Foundation for Distinguished Young Talents in Higher Education of Guangdong (No. C1085229 to ZZ).

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    1. MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China

      S. Wang, Z. Zou, H. Chang & D. Xing

    2. Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China

      X. Luo

    3. Department of Thoracic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China

      Y. Mi

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    Wang, S., Zou, Z., Luo, X. et al. LRH1 enhances cell resistance to chemotherapy by transcriptionally activating MDC1 expression and attenuating DNA damage in human breast cancer. Oncogene 37, 3243–3259 (2018). https://doi.org/10.1038/s41388-018-0193-4

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