TY - JOUR
T1 - Active vitamin D induces gene-specific hypomethylation in prostate cancer cells developing vitamin D resistance
AU - Lai, Guan Rong
AU - Lee, Yi Fen
AU - Yan, Shian Jang
AU - Ting, Huei Ju
N1 - Funding Information:
classical vitamin D hydroxyl metabolites provides a potential mechanism via which vitamin D suppresses DNMT expression (52, 53). Elucidation of these mechanisms of 1,25(OH)2D3-mediated DNMT1 downregulation requires further investigation. Overexpression of CYP24A1 and corepressors, such as NCoR1, has been linked to vitamin D resistance in PCa (32, 56), and 1,25(OH)2D3-mediated suppression of DNMTs may be a key to further clarifying the mechanisms involved. Our study demonstrated that overexpression of NCoR1 in treatment-resistant cells was not caused by DNA hypomethylation near the transcription start site of NCoR1 (Supplemental Fig. S2). However, our methylation microarray data showed a distal hypomethylated region of the NCoR1 promoter in vitamin D-resistant cells (Supplemental Table S1), indicating the potential for hypomethylation of other CpG sites to upregulate NCoR1. Other molecules that may mediate 1,25(OH)2D3-regulated NCoR1 expression include the miRNA-processing protein Dicer and the miRNA miR-199a. This connection is supported by
Publisher Copyright:
© 2020 the American Physiological Society.
PY - 2020/5
Y1 - 2020/5
N2 - Prostate cancer (PCa) is a leading cause of cancer death in men. Despite the antiproliferative effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on PCa, accumulating evidence indicates that 1,25(OH)2D3 promotes cancer progression by increasing genome plasticity. Our investigation of epigenetic changes associated with vitamin D insensitivity found that 1,25(OH)2D3 treatment reduced the expression levels and activities of DNA methyltransferases 1 and 3B (DNMT1 and DNMT3B, respectively). In silico analysis and reporter assay confirmed that 1,25(OH)2D3 downregulated transcriptional activation of the DNMT3B promoter and upregulated microRNAs targeting the 3=-untranslated regions of DNMT3B. We then profiled DNA methylation in the vitamin D-resistant PC-3 cells and a resistant PCa cell model generated by long-term 1,25(OH)2D3 exposure. Several candidate genes were found to be hypomethylated and overexpressed in vitamin D-resistant PCa cells compared with vitamin D-sensitive cells. Most of the identified genes were associated with mammalian target of rapamycin (mTOR) signaling activation, which is known to promote cancer progression. Among them, we found that inhibition of ribosomal protein S6 kinase A1 (RPS6KA1) promoted vitamin D sensitivity in PC-3 cells. Furthermore, The Cancer Genome Atlas (TCGA) prostate cancer data set demonstrated that midline 1 (MID1) expression is positively correlated with tumor stage. Overall, our study reveals an inhibitory mechanism of 1,25(OH)2D3 on DNMT3B, which may contribute to vitamin D resistance in PCa.
AB - Prostate cancer (PCa) is a leading cause of cancer death in men. Despite the antiproliferative effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on PCa, accumulating evidence indicates that 1,25(OH)2D3 promotes cancer progression by increasing genome plasticity. Our investigation of epigenetic changes associated with vitamin D insensitivity found that 1,25(OH)2D3 treatment reduced the expression levels and activities of DNA methyltransferases 1 and 3B (DNMT1 and DNMT3B, respectively). In silico analysis and reporter assay confirmed that 1,25(OH)2D3 downregulated transcriptional activation of the DNMT3B promoter and upregulated microRNAs targeting the 3=-untranslated regions of DNMT3B. We then profiled DNA methylation in the vitamin D-resistant PC-3 cells and a resistant PCa cell model generated by long-term 1,25(OH)2D3 exposure. Several candidate genes were found to be hypomethylated and overexpressed in vitamin D-resistant PCa cells compared with vitamin D-sensitive cells. Most of the identified genes were associated with mammalian target of rapamycin (mTOR) signaling activation, which is known to promote cancer progression. Among them, we found that inhibition of ribosomal protein S6 kinase A1 (RPS6KA1) promoted vitamin D sensitivity in PC-3 cells. Furthermore, The Cancer Genome Atlas (TCGA) prostate cancer data set demonstrated that midline 1 (MID1) expression is positively correlated with tumor stage. Overall, our study reveals an inhibitory mechanism of 1,25(OH)2D3 on DNMT3B, which may contribute to vitamin D resistance in PCa.
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U2 - 10.1152/ajpcell.00522.2019
DO - 10.1152/ajpcell.00522.2019
M3 - Article
C2 - 32159363
AN - SCOPUS:85083913101
VL - 318
SP - C836-C847
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6143
IS - 5
ER -