VDR Signaling via the Enzyme NAT2 Inhibits Colorectal Cancer Progression

Recent epidemiological and preclinical evidence indicates that vitamin D-3 inhibits colorectal cancer (CRC) progression, but the mechanism has not been completely elucidated. This study was designed to determine the protective effects of vitamin D-3 and identify crucial targets and regulatory mechanisms in CRC. First, we confirmed that 1,25(OH)(2)D-3, the active form of vitamin D-3, 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 D-3 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)(2)D-3 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 D-3 against CRC and introduce VDR signaling via the enzyme NAT2 as a potential diagnostic and therapeutic target for CRC.

Automated summary

The study found that vitamin D-3 inhibits CRC progression by promoting NAT2, possibly through the JAK1/STAT3 signaling pathway. Low expression of NAT2 was associated with higher metastasis risk and lower survival rates in CRC patients.