VDR-SOX2 signaling promotes colorectal cancer stemness and malignancy in an acidic microenvironment.

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.

• Authors: Pei-Shan Hu, Ting Li, Jin-Fei Lin, Miao-Zhen Qiu, De-Shen Wang, Ze-Xian Liu, Zhan-Hong Chen, Lu-Ping Yang, Xiao-Long Zhang, Qi Zhao, Yan-Xing Chen, Yun-Xin Lu, Qi-Nian Wu, Heng-Ying Pu, Zhao-Lei Zeng, Dan Xie, Huai-Qiang Ju, Hui-Yan Luo, Rui-Hua Xu
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 5 Issue 1 Pg. 183 (09 09 2020) ISSN: 2059-3635 [Electronic] England
• PMID: 32900990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acids
• Chromatin
• Organoplatinum Compounds
• PPAR delta
• Pyridines
• Receptors, Calcitriol
• SOX2 protein, human
• SOXB1 Transcription Factors
• VDR protein, human
• oxiplatin

Topics

• Acidosis (genetics, pathology)
• Acids (metabolism)
• Cell Proliferation (genetics)
• Chromatin (genetics)
• Colorectal Neoplasms (genetics, pathology)
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• HCT116 Cells
• Humans
• Male
• Middle Aged
• Neoplastic Stem Cells (metabolism, pathology)
• Organoplatinum Compounds (pharmacology)
• PPAR delta (genetics)
• Pyridines (pharmacology)
• Receptors, Calcitriol (genetics)
• SOXB1 Transcription Factors (genetics)
• Signal Transduction (drug effects)
• Tumor Microenvironment (genetics)
• Xenograft Model Antitumor Assays