Vitamin D receptor regulates methyltransferase like 14 to mitigate colitis-associated colorectal cancer

Zheng Wang; Lingjuan Jiang; Xiaoyin Bai; Mingyue Guo; Runing Zhou; Qingyang Zhou; Hong Yang; Jiaming Qian

doi:10.1016/j.jgg.2024.12.020

Volume 52 Issue 8

Aug. 2025

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2025 > 52(8): 1011-1020

PDF( 0 KB)

Vitamin D receptor regulates methyltransferase like 14 to mitigate colitis-associated colorectal cancer

doi: 10.1016/j.jgg.2024.12.020

a. Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China;
b. Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China;
c. Biomarker Discovery and Validation Facility, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

Funds:

The Integrated Entrusted Project of Research Funding at Peking Union Medical College Hospital (ZC201903347)

CAMS Innovation Fund for Medical Sciences (2021-I2M-1-001)

Health Research &

We thank the Pathology Department, Biomarker Discovery and Validation Facility, Laboratory Animal Research Facility of Institute of Clinical Medicine of PUMCH for supporting this study. We sincerely thank Prof. Tong and the members of the Department of Pathology at the Center for Experimental Animal Research, Institute of Basic Medical Sciences, PUMC. This work was funded by National High-Level Hospital Clinical Research Funding (2022-PUMCH-A-203)

Special Projects Grant of China (201002020 and 201502005)

Capital Health Development Scientific Research Fund (2022-2-4014)

the National Natural Science Foundation of China (81970495)

and Peking Union Medical College Hospital Research Funding for Postdoc (kyfyjj202315).

Received Date: 2024-07-17
Accepted Date: 2024-12-30
Rev Recd Date: 2024-12-27
Publish Date: 2025-01-06

Abstract

Abstract

Colitis-associated colorectal cancer (CAC), a serious complication of ulcerative colitis (UC), is associated with a poor prognosis. The vitamin D receptor (VDR) is recognized for its protective role in UC and CAC through the maintenance of intestinal barrier integrity and the regulation of inflammation. This study demonstrates a significant reduction in m⁶A-related genes, particularly methyltransferase like 14 (METTL14), in UC and CAC patients and identifies an association between METTL14 and VDR. In the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced mouse model, vitamin D treatment increases METTL14 expression and reduces tumor burden, while Vdr-knockout mice exhibit lower METTL14 levels and increased tumorigenesis. In vitro, the VDR agonist calcipotriol upregulates METTL14 in NCM460 cells, with this effect attenuated by VDR knockdown. VDR knockdown in DLD-1 colon cancer cells decreases METTL14 expression and promotes proliferation, which is reversed by METTL14 overexpression. Mechanistic studies reveal that VDR regulates METTL14 expression via promoter binding, modulating key target genes such as SOX4, DROSH, and PHLPP2. This study highlights the role of the VDR–METTL14 axis as a protective mechanism in CAC and suggests its potential as a therapeutic target for preventing and treating CAC.
- Inflammatory bowel disease,
- Vitamin D receptor,
- Methyltransferase like 14,
- Colitis-associated colorectal cancer,
- N⁶-methyladenosine methylation (m⁶A)

FullText(HTML)

References(44)

References

Bakke, D., Sun, J., 2018. Ancient nuclear receptor VDR with new functions: microbiome and inflammation. Inflamm. Bowel. Dis. 24, 1149-1154.

Beaugerie, L., Itzkowitz, S.H., 2015. Cancers complicating inflammatory bowel disease. N. Engl. J. Med. 373, 195.

Biton, M., Levin, A., Slyper, M., Alkalay, I., Horwitz, E., Mor, H., Kredo-Russo, S., Avnit-Sagi, T., Cojocaru, G., Zreik, F., et al., 2011. Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk. Nat. Immunol. 12, 239-246.

Carlberg, C., Munoz, A., 2022. An update on vitamin D signaling and cancer. Semin. Cancer Biol. 79, 217-230.

Castellano-Castillo, D., Morcillo, S., Crujeiras, A.B., Sanchez-Alcoholado, L., Clemente-Postigo, M., Torres, E., Tinahones, F.J., Macias-Gonzalez, M., 2019. Association between serum 25-hydroxyvitamin D and global DNA methylation in visceral adipose tissue from colorectal cancer patients. BMC. Cancer 19, 93.

Chen, X., Xu, M., Xu, X., Zeng, K., Liu, X., Pan, B., Li, C., Sun, L., Qin, J., Xu, T., et al., 2020. METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. Mol. Cancer. 19, 106.

Chong, M.M., Rasmussen, J.P., Rudensky, A.Y., Littman, D.R., 2008. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J. Exp. Med. 205, 2005-2017.

Cui, Q., Shi, H., Ye, P., Li, L., Qu, Q., Sun, G., Sun, G., Lu, Z., Huang, Y., Yang, C.G., et al., 2017. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell. Rep. 18, 2622-2634.

Deeb, K.K., Trump, D.L., Johnson, C.S., 2007. Vitamin D signaling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Cancer 7, 684-700.

Du, J., Sarkar, R., Li, Y., He, L., Kang, W., Liao, W., Liu, W., Nguyen, T., Zhang, L., Deng, Z., et al., 2022. N(6)-adenomethylation of GsdmC is essential for Lgr5(+) stem cell survival to maintain normal colonic epithelial morphogenesis. Dev. Cell 57, 1976-1994.

Feagins, L.A., Souza, R.F., Spechler, S.J., 2009. Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer. Nat. Rev. Gastroenterol. Hepatol. 6, 297-305.

Gong, D., Zhang, J., Chen, Y., Xu, Y., Ma, J., Hu, G., Huang, Y., Zheng, J., Zhai, W., Xue, W., 2019. The m(6)A-suppressed P2RX6 activation promotes renal cancer cells migration and invasion through ATP-induced Ca(2+) influx modulating ERK1/2 phosphorylation and MMP9 signaling pathway. J. Exp. Clin. Cancer Res. 38, 233.

Guan, Q., Lin, H., Miao, L., Guo, H., Chen, Y., Zhuo, Z., He, J., 2022. Functions, mechanisms, and therapeutic implications of METTL14 in human cancer. J. Hematol. Oncol. 15, 13.

Gyorffy, B., 2024. Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors. Innovation 5, 100625.

He, L., Li, H., Wu, A., Peng, Y., Shu, G., Yin, G., 2019. Functions of N6-methyladenosine and its role in cancer. Mol. Cancer 18, 176.

Hossain, S., Liu, Z., Wood, R.J., 2021. Association between histone deacetylase activity and vitamin D-dependent gene expressions in relation to sulforaphane in human colorectal cancer cells. J. Sci. Food Agric. 101, 1833-1843.

Hou, Y., Zhang, X., Yao, H., Hou, L., Zhang, Q., Tao, E., Zhu, X., Jiang, S., Ren, Y., Hong, X., et al., 2023. METTL14 modulates glycolysis to inhibit colorectal tumorigenesis in p53-wild-type cells. EMBO Rep. 24, e56325.

Hu, B.B., Wang, X.Y., Gu, X.Y., Zou, C., Gao, Z.J., Zhang, H., Fan, Y., 2019. N(6)-methyladenosine (m(6)A) RNA modification in gastrointestinal tract cancers: roles, mechanisms, and applications. Mol. Cancer 18, 178.

Hu, P.S., Li, T., Lin, J.F., Qiu, M.Z., Wang, D.S., Liu, Z.X., Chen, Z.H., Yang, L.P., Zhang, X.L., Zhao, Q., et al., 2020. VDR-SOX2 signaling promotes colorectal cancer stemness and malignancy in an acidic microenvironment. Signal Transduct. Target Ther. 5, 183.

Iyer, D.N., Foo, D.C., Lo, O.S., Wan, T.M., Li, X., Sin, R.W., Pang, R.W., Law, W.L., Ng, L., 2022. MiR-509-3p is oncogenic, targets the tumor suppressor PHLPP2, and functions as a novel tumor adjacent normal tissue based prognostic biomarker in colorectal cancer. BMC. Cancer 22, 351.

Li, Q., Chan, H., Liu, W.X., Liu, C.A., Zhou, Y., Huang, D., Wang, X., Li, X., Xie, C., Liu, W.Y., et al., 2023. Carnobacterium maltaromaticum boosts intestinal vitamin D production to suppress colorectal cancer in female mice. Cancer Cell 41, 1450-1465.

Li, X., Stevens, P.D., Liu, J., Yang, H., Wang, W., Wang, C., Zeng, Z., Schmidt, M.D., Yang, M., Lee, E.Y., et al., 2014. PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice. Gastroenterology 146, 1301-1312.

Lin, S., Gregory, R.I., 2015. MicroRNA biogenesis pathways in cancer. Nat. Rev. Cancer 15, 321-333.

Liu, J., Weiss, H.L., Rychahou, P., Jackson, L.N., Evers, B.M., Gao, T., 2009. Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis. Oncogene 28, 994-1004.

Ma, Y., Zhang, X., Xuan, B., Li, D., Yin, N., Ning, L., Zhou, Y.L., Yan, Y., Tong, T., Zhu, X., et al., 2024. Disruption of CerS6-mediated sphingolipid metabolism by FTO deficiency aggravates ulcerative colitis. Gut 73, 268-281.

Monaghan, T.M., Seekatz, A.M., Markham, N.O., Yau, T.O., Hatziapostolou, M., Jilani, T., Christodoulou, N., Roach, B., Birli, E., Pomenya, O., et al., 2021. Fecal microbiota transplantation for recurrent clostridioides difficile infection associates with functional alterations in circulating microRNAs. Gastroenterology 161, 255-270.

Morris, N.L., Hammer, A.M., Cannon, A.R., Gagnon, R.C., Li, X., Choudhry, M.A., 2017. Dysregulation of microRNA biogenesis in the small intestine after ethanol and burn injury. Biochim. Biophys. Acta. Mol. Basis. Dis. 1863, 2645-2653.

Siegel, R.L., Miller, K.D., Fuchs, H.E., Jemal, A., 2021. Cancer Statistics, 2021. CA. Cancer J. Clin. 71, 7-33.

Sun, M., Guo, B., 2017. Vitamin D and the epigenetic machinery in colon cancer. Curr. Med. Chem. 24, 888-897.

Sun, T., Wu, Z., Wang, X., Wang, Y., Hu, X., Qin, W., Lu, S., Xu, D., Wu, Y., Chen, Q., et al., 2020. LNC942 promoting METTL14-mediated m(6)A methylation in breast cancer cell proliferation and progression. Oncogene 39, 5358-5372.

Terzic, J., Grivennikov, S., Karin, E., Karin, M., 2010. Inflammation and colon cancer. Gastroenterology 138, 2101-2114.

Van Der Kraak, L., Gros, P., Beauchemin, N., 2015. Colitis-associated colon cancer: Is it in your genes? World J. Gastroenterol. 21, 11688-11699.

Wang, S., Gan, M., Chen, C., Zhang, Y., Kong, J., Zhang, H., Lai, M., 2021. Methyl CpG binding protein 2 promotes colorectal cancer metastasis by regulating N(6) -methyladenosine methylation through methyltransferase-like 14. Cancer Sci. 112, 3243-3254.

Wang, X., Lu, Z., Gomez, A., Hon, G.C., Yue, Y., Han, D., Fu, Y., Parisien, M., Dai, Q., Jia, G., et al., 2014. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117-120.

Wang, Z., Yang, H., Lv, H., Huang, C., Qian, J., 2022. Vitamin D receptor-dependent protective effect of moderate hypoxia in a mouse colitis model. Front. Physiol. 13, 876890.

Weng, H., Huang, H., Wu, H., Qin, X., Zhao, B.S., Dong, L., Shi, H., Skibbe, J., Shen, C., Hu, C., et al., 2018. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification. Cell Stem Cell 22, 191-205.

Wierzbicka, J.M., Binek, A., Ahrends, T., Nowacka, J.D., Szydlowska, A., Turczyk, L., Wasiewicz, T., Wierzbicki, P.M., Sadej, R., Tuckey, R.C., et al., 2015. Differential antitumor effects of vitamin D analogues on colorectal carcinoma in culture. Int. J. Oncol. 47, 1084-1096.

Xin, Y., He, L., Luan, Z., Lv, H., Yang, H., Zhou, Y., Zhao, X., Zhou, W., Yu, S., Tan, B., et al., 2017. E-cadherin mediates the preventive effect of vitamin D3 in colitis-associated carcinogenesis. Inflamm. Bowel. Dis. 23, 1535-1543.

Yang, X., Zhang, S., He, C., Xue, P., Zhang, L., He, Z., Zang, L., Feng, B., Sun, J., Zheng, M., 2020. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol. Cancer. 19, 46.

Zhang, C., Zhang, M., Ge, S., Huang, W., Lin, X., Gao, J., Gong, J., Shen, L., 2019. Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K-Akt signaling in gastric cancer. Cancer Med. 8, 4766-4781.

Zhang, T., Ding, C., Chen, H., Zhao, J., Chen, Z., Chen, B., Mao, K., Hao, Y., Roulis, M., Xu, H., et al., 2022a. m(6)A mRNA modification maintains colonic epithelial cell homeostasis via NF-kappaB-mediated antiapoptotic pathway. Sci. Adv. 8, eabl5723.

Zhang, X., Li, D., Jia, C., Cai, H., Lv, Z., Wu, B., 2021. METTL14 promotes tumorigenesis by regulating lncRNA OIP5-AS1/miR-98/ADAMTS8 signaling in papillary thyroid cancer. Cell Death Dis. 12, 617.

Zhang, Y., Garrett, S., Carroll, R.E., Xia, Y., Sun, J., 2022b. Vitamin D receptor upregulates tight junction protein claudin-5 against colitis-associated tumorigenesis. Mucosal Immunol. 15, 683-697.

Zhang, Y.G., Lu, R., Wu, S., Chatterjee, I., Zhou, D., Xia, Y., Sun, J., 2020. Vitamin D receptor protects against dysbiosis and tumorigenesis via the JAK/STAT pathway in intestine. Cell. Mol. Gastroenterol. Hepatol. 10, 729-746.

Relative Articles

Supplements(0)

Cited By

Proportional views