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A regulatory circuit HP1γ/miR-451a/c-Myc promotes prostate cancer progression

Oncogene volume 37, pages 415–426 (2018)Cite this article

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Abstract

Heterochromatin protein 1γ (HP1γ) has been implicated in carcinogenesis of various cancer types. However, the role of HP1γ in prostate cancer (PCa) progression and the underlying molecular mechanisms remain largely unknown. We found that HP1γ is upregulated in PCa and elevated levels of HP1γ in PCa predict poor outcome. In addition, depletion of HP1γ in PCa cells not only repressed proliferation and induced apoptosis but also impaired tumorigenicity. We also found that c-Myc was capable of upregulating HP1γ by directly binding to the E-box element in the first intron of HP1γ gene, and the upregulated HP1γ, in turn, repressed the expression of miR-451a by enhancing H3K9 methylation at the promoter region of miR-451a. Furthermore, reduction of miR-451a significantly reversed HP1γ loss-induced PCa cell apoptosis, whereas miR-451a overexpression repressed cell survival by targeting and downregulating c-Myc. The association among c-Myc, HP1γ and miR-451a was further confirmed in human clinical samples. Therefore, we propose that an HP1γ/miR-451a/c-Myc regulatory circuitry exists in PCa cells and this circuit has a crucial role in PCa progression.

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Acknowledgements

This study was financially supported by the National Key Research and Development Plan of China (2016YFC0902202 to JY), the National Natural Science Foundation of China (81172009, 81672873 and 81372168 to JY, and 81172442 to JJ), Doctoral Fund of Ministry of Education of China (20110091120028 to JY), Natural Science Foundation for Universities in Jiangsu Province, China (BK20151396 to JY), the Center for Chronic Disorders of Aging (CCDA) at Philadelphia College of Osteopathic Medicine (to DZ), the ‘Personalized Medicines—Molecular Signature-based Drug Discovery and Development’, Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDA12020108 (to RH), One Hundred Talent Program of Chinese Academy of Sciences (to RH), Program sponsored for Scientific Innovation Research of College Graduate in Jiangsu province (KYZZ_0037 to CC), the Open Foundation of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University (KF-GN-201602) and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (SIMM1705KF-02). We also thank Jun Qin and Min Jiang for their help in data retrieval from TCGA database.

Author contributions

RH, DZ and JY designed the study. CC and WH performed the experiments. CC, XH and MQ performed IHC on human prostate cancer slides; JJ performed IHC on human prostate cancer tissue array; CC, JL and LS performed PCR array; and CC, YD and JJ analyzed the data and performed the statistics. CC, YD, X-YF, HG, RH, DZ and JY analyzed and interpreted the data. CC, RH, DZ and JY wrote the manuscript. JY supervised the study.

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Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China

    C Chang, J Liu, W He, X Huang, L Shen, X Y Fu & J Yan

  2. Collaborative Innovation Center of Genetics and Development, Shanghai, China

    C Chang, J Liu, X Huang, L Shen & J Yan

  3. Department of Bioscience and Bioengineering, School of Chemistry and Life Science, Jinling College of Nanjing University, Nanjing, China

    M Qu

  4. Department of Urology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, China

    Y Deng, X Zhao & H Guo

  5. Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China

    J Jiang

  6. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    R Huang

  7. Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA

    D Zhang

  8. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    J Yan

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  1. C Chang
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Correspondence to J Yan.

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Chang, C., Liu, J., He, W. et al. A regulatory circuit HP1γ/miR-451a/c-Myc promotes prostate cancer progression. Oncogene 37, 415–426 (2018). https://doi.org/10.1038/onc.2017.332

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