AUTHOR=Zhu Chaojun , Wang Zihuan , Cai Jianqun , Pan Chunqiu , Lin Simin , Zhang Yue , Chen Yuting , Leng Mengxin , He Chengcheng , Zhou Peirong , Wu Changjie , Fang Yuxin , Li Qingyuan , Li Aimin , Liu Side , Lai Qiuhua TITLE=VDR Signaling via the Enzyme NAT2 Inhibits Colorectal Cancer Progression JOURNAL=Frontiers in Pharmacology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.727704 DOI=10.3389/fphar.2021.727704 ISSN=1663-9812 ABSTRACT=

Recent epidemiological and preclinical evidence indicates that vitamin D3 inhibits colorectal cancer (CRC) progression, but the mechanism has not been completely elucidated. This study was designed to determine the protective effects of vitamin D3 and identify crucial targets and regulatory mechanisms in CRC. First, we confirmed that 1,25(OH)2D3, the active form of vitamin D3, suppressed the aggressive phenotype of CRC in vitro and in vivo. Based on a network pharmacological analysis, N-acetyltransferase 2 (NAT2) was identified as a potential target of vitamin D3 against CRC. Clinical data of CRC patients from our hospital and bioinformatics analysis by online databases indicated that NAT2 was downregulated in CRC specimens and that the lower expression of NAT2 was correlated with a higher metastasis risk and lower survival rate of CRC patients. Furthermore, we found that NAT2 suppressed the proliferation and migration capacity of CRC cells, and the JAK1/STAT3 signaling pathway might be the underlying mechanism. Moreover, Western blot and immunofluorescence staining assays demonstrated that 1,25(OH)2D3 promoted NAT2 expression, and the chromatin immunoprecipitation assay indicated that the vitamin D receptor (VDR) transcriptionally regulated NAT2. These findings expand the potential uses of vitamin D3 against CRC and introduce VDR signaling via the enzyme NAT2 as a potential diagnostic and therapeutic target for CRC.