VDR Signaling via the Enzyme NAT2 Inhibits Colorectal Cancer Progression

Chaojun Zhu,Simin Lin,Yuxin Fang,Zihuan Wang,Peirong Zhou,Chengcheng He,Qingyuan Li,Mengxin Leng,Changjie Wu,Aimin Li,Jianqun Cai,Qiuhua Lai,Yuting Chen,Yue Zhang,Side Liu,Chunqiu Pan

doi:10.3389/fphar.2021.727704

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.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer death worldwide (Laversanne et al, 2020; Sung et al, 2021)
Populations with lower circulating vitamin D concentration are at higher risk of colorectal cancer (CRC) (Garland et al, 1985; Jenab et al, 2010), and vitamin D deficiency predicts shortened overall survival in CRC patients (Ng et al, 2008; Zgaga et al, 2014)
Another prospective clinical trial aimed to determine whether high-dose vitamin D3 could improve outcomes in patients undergoing standard chemotherapy for metastatic CRC

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer death worldwide (Laversanne et al, 2020; Sung et al, 2021). The 5year survival rate of CRC has been increasing in recent years (Brenner et al, 2014; Laversanne et al, 2020), poor prognosis always brings a heavy burden to patients and health care. Both genetic and environmental factors are known to be involved in CRC initiation and progression (Lichtenstein et al, 2000; Brenner et al, 2014). It is essential to further reveal the biological mechanisms illustrating the antitumor role of vitamin D3 in CRC

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