School of Chinese Medicine
1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through MicroRNA-498
Telomerase is an essential enzyme that counteracts the telomere attrition accompanying DNA replication during cell division. Regulation of the promoter activity of the gene encoding its catalytic subunit, the telomerase reverse transcriptase, is established as the dominant mechanism conferring the high telomerase activity in proliferating cells, such as embryonic stem and cancer cells. This study reveals a new mechanism of telomerase regulation through non-coding small RNA by showing that microRNA-498 (miR-498) induced by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) decreases the mRNA expression of the human telomerase reverse transcriptase. MiR-498 was first identified in a microarray analysis as the most induced microRNA by 1,25(OH)2D3 in ovarian cancer cells and subsequently validated by quantitative polymerase chain reaction assays in multiple human cancer types. A functional vitamin D response element was defined in the 5-prime regulatory region of the miR-498 genome, which is occupied by the vitamin D receptor and its coactivators. Further studies showed that miR-498 targeted the 3-prime untranslated region of human telomerase reverse transcriptase mRNA and decreased its expression. The levels of miR-498 expression were decreased in malignant human ovarian tumors as well as human ovarian cancer cell lines. The ability of 1,25(OH)2D3 to decrease human telomerase reverse transcriptase mRNA and to suppress ovarian cancer growth was compromised when miR-498 was depleted using the sponges in cell lines and mouse tumor models. Taken together, our studies define a novel mechanism of telomerase regulation by small non-coding RNAs and identify miR-498 as an important mediator for the anti-tumor activity of 1,25(OH)2D3. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Source Publication Title
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology
Kasiappan, Ravi, Zheng Shen, Anfernee K.-W. Tse, Umesh Jinwal, Jinfu Tang, Panida Lungchukiet, Yuefeng Sun, Patricia Kruk, Santo V. Nicosia, Xiaohong Zhang, and Wenlong Bai. "1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through MicroRNA-498." Journal of Biological Chemistry 287.49 (2012): 41297-41309.