VITAMIN D SUPPRESSES CANCER GROWTH AND INVASION BY TARGETING LONG NON-CODING RNA CCAT2

Calcitriol (1 alpha, 25-dihydroxy vitamin D3, 1α,25-(OH)2D3), the most active metabolite of vitamin D (VD), protects against various types of cancers. Preclinical studies have presented that calcitriol suppresses cancer growth in a cell- and tissue-specific manner. Here, our study determined that the anti-growth and anti-invasion effects of calcitriol in ovarian cancer (Oca) and colon cancer (CRC) cells. Moreover, previous studies suggested that calcitriol may exhibit genomic effects on both protein-coding genes and non-coding genes. However, the epigenetic mechanisms of calcitriol’s anti-cancer effects remain largely unknown as its downstream targets or signaling pathways are poorly identified. To explore the potential epigenetic mechanism of vitamin D, we investigated the effects of calcitriol on long noncoding RNA (lncRNA) expression profiles in ovarian and colon cancer cells. We firstly identified that calcitriol could regulate specific lncRNAs and the corresponding downstream pathways in its cancer-preventive action. In our study, we illustrated that (a) Treatment with calcitriol inhibited ovarian and colon cancer cell proliferation, migration, and invasion; (b) calcitriol induced cell cycle arrest in a cell-specific manner; (c) lncRNA CCAT2 (colon cancer-associated transcript 2) is significantly down-regulated in the presence of calcitriol in ovarian and colon cancer cells; (d) lncRNA CCAT2 exerted a regulatory potential on MYC gene expression; (e) calcitriol inhibited the physical interaction of CCAT2 and its downstream transcription factor TCF4; (f) As a result of CCAT2 inhibition, the binding of CCAT2:TCF4 ribonucleoprotein to the MYC promoter was suppressed at the action of calcitriol, resulting in the repression of MYC expression. Our results offered a novel mechanism in vitamin D-mediated anti-cancer activities by targeting lncRNA CCAT2. Colon tumor xenografts studies supported the results of in vitro studies that calcitriol inhibited CCAT2 expression and, consequently caused a decrease in c-Myc (encoded by MYC) expression. Our findings strongly suggested that vitamin D could be considered as a practical and inexpensive nutraceutical for cancer prevention and treatment.