VDR–SOX2 signaling promotes colorectal cancer stemness and malignancy in an acidic microenvironment
Open Access
- 9 September 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Signal Transduction and Targeted Therapy
- Vol. 5 (1), 1-13
- https://doi.org/10.1038/s41392-020-00230-7
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.Keywords
This publication has 46 references indexed in Scilit:
- Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancerNature Genetics, 2012
- Sox2 expression in breast tumours and activation in breast cancer stem cellsOncogene, 2011
- Microenvironmental regulation of stem cells in intestinal homeostasis and cancerNature, 2011
- Regulation of cancer cell metabolismNature Reviews Cancer, 2011
- SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomasNature Genetics, 2009
- The Genomic Analysis of Lactic Acidosis and Acidosis Response in Human CancersPLoS Genetics, 2008
- Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonateNature, 2008
- Protein Under-Wrapping Causes Dosage Sensitivity and Decreases Gene DuplicabilityPLoS Genetics, 2008
- Induced Pluripotent Stem Cell Lines Derived from Human Somatic CellsScience, 2007
- Vitamin D signalling pathways in cancer: potential for anticancer therapeuticsNature Reviews Cancer, 2007