Fig. 3

Tracing the fate of 1,25(OH)₂D_3, the active form of vitamin D in target cells. The lipophilic nature of 1,25(OH)₂D₃ helps it to passively cross cell membrane without a transporter and bind to VDR in the cytoplasm and/or the nucleus. As a nuclear transcription factor, VDR regulates the transcription of target genes in a ligand-dependent manner. Upon binding to 1,25(OH)₂D₃, VDR enters the nuclei and heterodimerizes with the retinoid X receptor (RXR). The active VDR/RXR complex is then able to bind specific consensus sequences, vitamin D response elements (VDREs), at the promoters of its direct target genes. It also initiates the recruitment of co-activators or co-repressors to modulate the target genes so as to maintain homeostasis. Beyond VDR, its classical partner, 1,25(OH)₂D₃ can also bind to membrane-embedded receptors and affect cytoplasmic signaling cascades through its non-transcriptional activities [39]. Direct or indirect downstream lncRNA targets of the vitamin D/VDR signaling pathways include AS-HSD17β2 in prostate cancer [40], H19 in colon cancer [41], lncBCAS1-4_1 [42] and TOPORS-AS1 [43] in ovarian cancer, LUCAT1 in oral squamous cell carcinoma (OSCC) [44], MEG3 in colorectal cancer (CRC) [45], MALAT1 in coronary artery disease (CAD) [46], and HOTAIR in multiple sclerosis [47]. Created with BioRender.com