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Chromatin composition alterations and the critical role of MeCP2 for epigenetic silencing of progesterone receptor-B gene in endometrial cancers

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Abstract

Objective

To understand the epigenetic mechanism underlying the PR-B gene silencing in endometrial cancer (EC) cells, we compared the chromatin composition between transcriptionally active and silenced PR-B genes in EC cell lines and cancer tissues.

Methods

Chromatin Immunoprecipitation (ChIP) assay was performed to measure MBD occupancy and histone acetylation/methylation in transcriptionally active and silenced PR-B genes. PR-B-positive/-negative, as well as epigenetic inhibitor-treated/-untreated EC cells were used as study models. Real-time polymerase chain reaction (PCR) and Western blot analysis were applied to measure the mRNA and protein levels of PR-B, MBD, and histones.

Results

A close association among PR-B methylation, MBD binding and PR-B gene silencing was observed. Treatment with epigenetic inhibitors led to dynamic changes in the PR-B chromatin composition and gene expression. Increased H3/H4 acetylation and H3-K4 methylation, and decreased H3-K9 methylation were found to be associated with re-activation of silenced PR-B genes. MeCP2 knockdown resulted in a decreased MeCP2 binding to PR-B genes and an increased PR-B expression. ChIP analysis of MeCP2 binding to PR-B genes in the PR-B-positive/-negative EC samples confirmed the significant role of MeCP2 in PR-B silencing.

Conclusion

PR-B gene expression is regulated by a concerted action of epigenetic factors including DNA methylation, MBD binding, and histone modifications. MeCP2 occupancy of PR-B genes plays a critical role in PR-B gene silencing. These findings enriched our knowledge of the epigenetic regulation of PR-B expression in EC, and suggested that the epigenetic re-activation of PR-B could be explored as a potential strategy to sensitize the PR-B-negative endometrial cancers to progestational therapy.

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Acknowledgments

The authors would like thank Mrs. Lynn Caflisch for her strong secretarial support and Mrs. Ying Zhao for her superb technical assistance. Shi-Wen Jiang is supported by the Distinguished Cancer Scholarship of the Georgia Research Alliance (GRA). This work was partially funded by research grants from the National Institute of Health (NIH) (R01 HD 41577, Shi-Wen Jiang); the NIH/National Cancer Institute (NCI)-MD Anderson Uterine Cancer SPORE (Jinping Li, Shi-Wen Jiang); the NIH K12 training program (Sean Dowdy, Shi-Wen Jiang); a research grant from Merck Pharmaceiticals (Sean Dowdy, Shi-Wen Jiang); the research supplement from the Department of Obstetrics and Gynecology, Mayo Clinic and Mayo Medical School (Shi-Wen Jiang); the National Natural Science Foundation of China 81200420 and the Yantai Science Development Fund 2011219 (Yongli Chu); the Shangdong Natural Science Foundation ZR2012HL03 and 2011YD21014 (Yanlin Wang); the research start-up from Mercer University School of Medicine (Jinping Li); and seed grants from Mercer University (Jinping Li, Shi-Wen Jiang).

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, China

    Yongli Chu

  2. Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, China

    Yanlin Wang

  3. Tianjin Medical University Cancer Hospital, Tianjin, 300060, China

    Guanghua Zhang

  4. Department of Histology and Embryology, Shantou University Medical College, Guangdong, China

    Haibin Chen

  5. Department of Obstetrics and Gynecology, Mayo Clinic and Mayo Medical School, Rochester, MN, 55905, USA

    Sean C. Dowdy, Yuning Xiong, Jinping Li & Shi-Wen Jiang

  6. Department of Research and Development, Guangxi Medicinal Botanical Institute, Nanning, 530024, China

    Fengming Liu

  7. Curtis & Elizabeth Anderson Cancer Institute, Memorial Health University Medical Center, 4700 Waters Avenue, Savannah, GA, 31404, USA

    Jinping Li & Shi-Wen Jiang

  8. Department of Obstetrics and Gynecology, Memorial Health University Medical Center, 4700 Waters Avenue, Savannah, GA, 31404, USA

    Shi-Wen Jiang

  9. Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA, 31404, USA

    Run Zhang, Jinping Li & Shi-Wen Jiang

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  1. Yongli Chu
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  2. Yanlin Wang
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  3. Guanghua Zhang
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  4. Haibin Chen
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  6. Yuning Xiong
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  7. Fengming Liu
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  8. Run Zhang
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  9. Jinping Li
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  10. Shi-Wen Jiang
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Correspondence to Jinping Li or Shi-Wen Jiang.

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Y. Chu, Y. Wang, G. Zhang and H. Chen contributed equally.

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Chu, Y., Wang, Y., Zhang, G. et al. Chromatin composition alterations and the critical role of MeCP2 for epigenetic silencing of progesterone receptor-B gene in endometrial cancers. Cell. Mol. Life Sci. 71, 3393–3408 (2014). https://doi.org/10.1007/s00018-014-1580-9

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