MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice.

BACKGROUND & AIMS: Vitamin D protects against colorectal cancer through unclear mechanisms. We investigated the effects of calcitriol (1α,25-dihydroxyvitamin D3; the active form of vitamin D) on levels of different microRNAs (miRNAs) in colorectal cancer cells from humans and xenograft tumors in mice.

METHODS

Expression of miRNAs in colorectal cancer cell lines was examined using the Ambion mirVana miRNA Bioarray. The effects of calcitriol on expression of miR-627 and cell proliferation were determined by real-time polymerase chain reaction and WST-1 assay, respectively; growth of colorectal xenograft tumors was examined in nude mice. Real-time polymerase chain reaction was used to analyze levels of miR-627 in human colon adenocarcinoma samples and nontumor colon mucosa tissues (controls).

RESULTS

In HT-29 cells, miR-627 was the only miRNA significantly up-regulated by calcitriol. Jumonji domain containing 1A (JMJD1A), which encodes a histone demethylase, was found to be a target of miR-627. By down-regulating JMJD1A, miR-627 increased methylation of histone H3K9 and suppressed expression of proliferative factors, such as growth and differentiation factor 15. Calcitriol induced expression of miR-627, which down-regulated JMJD1A and suppressed growth of xenograft tumors from HCT-116 cells in nude mice. Overexpression of miR-627 prevented proliferation of colorectal cancer cell lines in culture and growth of xenograft tumors in mice. Conversely, blocking the activity of miR-627 inhibited the tumor suppressive effects of calcitriol in cultured colorectal cancer cells and in mice. Levels of miR-627 were decreased in human colon adenocarcinoma samples compared with controls.

CONCLUSIONS

miR-627 mediates tumor-suppressive epigenetic activities of vitamin D on colorectal cancer cells and xenograft tumors in mice. The messenger RNA that encodes the histone demethylase JMJD1A is a direct target of miR-627. Reagents designed to target JMJD1A or its messenger RNA, or increase the function of miR-627, might have the same antitumor activities of vitamin D without the hypercalcemic side effects.