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

Krishna M. Sinha, Rozita Bagheri-Yarmand, Sharmistha Lahiri, Yue Lu, Miao Zhang, Sarah Amra, Yasmeen Rizvi, Xinhai Wan, Nora Navone, Bulent Ozpolat, Christopher Logothetis, Robert F. Gagel, Johnny Huard

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5038-5049
Number of pages12
JournalOncogene
Volume38
Issue number25
DOIs
StatePublished - Jun 20 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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