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Oncogenic and osteolytic functions of histone demethylase NO66 in castration-resistant prostate cancer

Oncogene volume 38, pages 5038–5049 (2019)Cite this article

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Abstract

Epigenetic changes that cause dysregulated gene expression during progression of androgen-independent prostate cancer (PCa) and metastatic skeletal lesions remain elusive. Here, we explored the role of histone demethylase NO66 in the pathogenesis of PCa and bone metastasis-related skeletal lesions. Tissue and cDNA microarrays of PCa were analyzed for NO66 mRNA and protein levels. We examined the effects of gain and loss of NO66 function on cell viability, colony formation, migration, invasion, and tumor-induced skeletal lesions in femoral bone. RNAseq and ChIPseq were performed to elucidate NO66-target genes in PCa. We report that NO66 levels were upregulated in advanced primary prostate tumors compared to normal tissue or tumors with low Gleason scores. Forced expression of NO66 promoted cell survival and invasion of PCa cells; whereas, knockdown of NO66 resulted in decreased cell survival and increased sensitivity to docetaxel. NO66-overexpressing PC3 cells implanted into the femoral bone of male SCID mice caused massive bone loss and stimulation of mouse osteoclast-promoting genes, including Dickkopf1, Cathepsin K, Nf-kβ,; and Calcr, suggesting a role for NO66 in tumor growth in bone and osteoclast activity. Combined RNAseq and ChIP-seq revealed that NO66 activates the survival gene MCL1, the invasion-associated genes IGFBP5 and MMP3, the pro-oncogenic genes CTNNB1 and CCND1, and the epigenetic modifier gene KMT2A in androgen-independent PCa. Our findings uncover the role of NO66 as a key oncogenic driver in PCa, causing osteolytic lesions through upstream epigenetic regulation of key genes for survival, invasion and metastasis, and pro-osteoclastic factors.

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Acknowledgements

We thank Dr. Mary A. Hall for editorial assistance, Ling Zhong for microscopy, and Jun Yang for technical assistance.

Funding

This work was supported by National Institutes of Health Grant P50 CA140388 (NCI-SPORE- Developmental Research Program) to CL and KMS, Center for Epigenetics at MDACC allowance for Next-Gen sequencing to KMS, the Bone Diseases Program of Texas to RFG, and by UTHealth startup funding to JH.

Author’s contribution

KMS and RB-Y designed and performed experiments, analyzed data and wrote manuscript. YL performed bioinformatics analysis, MZ conducted histological analysis; SA performed histology; SL and YR provided technical assistance for experiments; NN and XW for cell lines and animal studies; BO, CL, RFG, and JH for administrative and material support; KMS, RB-Y, BO, and JH discussed and reviewed the manuscript.

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Authors and Affiliations

  1. Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Krishna M. Sinha, Rozita Bagheri-Yarmand, Sharmistha Lahiri, Yasmeen Rizvi & Robert F. Gagel

  2. Department of Orthopaedic Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Krishna M. Sinha, Sarah Amra & Johnny Huard

  3. Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yue Lu

  4. Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Miao Zhang, Xinhai Wan, Nora Navone & Christopher Logothetis

  5. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Bulent Ozpolat

  6. Steadman Philippon Research Institute, Vail, CO, USA

    Johnny Huard

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  1. Krishna M. Sinha
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Sinha, K.M., Bagheri-Yarmand, R., Lahiri, S. et al. Oncogenic and osteolytic functions of histone demethylase NO66 in castration-resistant prostate cancer. Oncogene 38, 5038–5049 (2019). https://doi.org/10.1038/s41388-019-0774-x

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