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.

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

“…Moreover, an acidic TME also alters the cellular proteome, cellular metabolism, and signaling pathways, facilitating stemness and drug resistance in cancer cells. The acidosis induces SOX2 expression by inhibiting vitamin D receptor (VDR)-mediated transcription, resulting in drug resistance ( Hu et al, 2020 ). Enhanced lactate uptake and oxidation-induced lactic acidosis foster the resistance to uprosertib, a pan-Akt inhibitor, in colon cancer cells ( Barnes et al, 2020 ).…”

MicroRNAs regulating SOX2 in cancer progression and therapy response

“…The SOX2 function in tumours has been confirmed in various experiments (Ref. 74). The accumulation of genetic alterations in cells leads to cell cycle changes that are in factor of tumour development.…”

NCOR1 Sustains Colorectal Cancer Cell Growth and Protects against Cellular Senescence

“…These observations coincide well with our data and suggest a possible functional regulatory axis between NCOR1 and SOX2 in the control of cellular senescence. Interestingly, a recent study showed that the SOX2 gene promoter was directly repressed from vitamin D receptor (VDR) occupancy on VDR elements in colon cancer cells [69]. VDR recruits NCOR1 to negatively regulate vitamin-D3-mediated transcription [70] and physical recruitment of NCOR1 on VDR gene targets was associated with altered repression of chromatin marks in prostate cancer [71].…”