骨化三醇受体
SOX2
癌症研究
染色质免疫沉淀
生物
肿瘤微环境
内分泌学
内科学
细胞生物学
转录因子
维生素D与神经学
基因表达
医学
生物化学
发起人
基因
肿瘤细胞
作者
Peishan Hu,Ting Li,Jin‐Fei Lin,Miaozhen Qiu,De-Shen Wang,Zexian Liu,Zhan-Hong Chen,Lu-Ping Yang,Xiaolong Zhang,Qi Zhao,Yan‐Xing Chen,Yong Lu,Qi‐Nian Wu,Heng‐Ying Pu,Zhao-Lei Zeng,Dan Xie,Huai-Qiang Ju,Hongyu Luo,Rui‐Hua Xu
标识
DOI:10.1038/s41392-020-00230-7
摘要
Abstract The acidic tumor microenvironment provides an energy source driving malignant tumor progression. Adaptation of cells to an acidic environment leads to the emergence of cancer stem cells. The expression of the vitamin D receptor (VDR) is closely related to the initiation and development of colorectal carcinoma (CRC), but its regulatory mechanism in CRC stem cells is still unclear. Our study revealed that acidosis reduced VDR expression by downregulating peroxisome proliferator-activated receptor delta (PPARD) expression. Overexpression of VDR effectively suppressed the stemness and oxaliplatin resistance of cells in acidosis. The nuclear export signal in VDR was sensitive to acidosis, and VDR was exported from the nucleus. Chromatin immunoprecipitation (ChIP) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses showed that VDR transcriptionally repressed SRY-box 2 ( SOX2 ) by binding to the vitamin D response elements in the promoter of SOX2 , impairing tumor growth and drug resistance. We demonstrated that a change in the acidic microenvironment combined with overexpression of VDR substantially restricted the occurrence and development of CRC in vivo. These findings reveal a new mechanism by which acidosis could affect the stemness of CRC cells by regulating the expression of SOX2 and show that abnormal VDR expression leads to ineffective activation of vitamin D signaling, resulting in a lack of efficacy of vitamin D in antineoplastic process.
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