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LncBCAS1-4_1, a Functional Homolog of CYP24A1, Attenuates the Anticancer Efficacy of 1,25(OH)₂D₃ in Lung Cancer via Glycolysis and EMT

ABSTRACT: Building on prior evidence implicating lncBCAS1-4_1 in resisting vitamin D signaling across cancer types, this study characterizes its mechanism of action in lung malignancies. Though induced by 1α,25(OH)2D3 treatment apart from CYP24A1 regulation, lncBCAS1-4_1 knockdown potentiated the growth-inhibitory impact of 1α,25(OH)2D3 on lung cancer cells. Orthotopic xenograft models validated lncBCAS1-4_1’s oncogenic potential, which was suppressible by supplemental vitamin D, but upregulated lncBCAS1-4_1 following 1,25(OH)2D3 treatment was independent of CYP24A1. Intriguingly, the knockdown of lncBCAS1-4_1 augmented the anti-proliferative and migrative effect of 1α,25(OH)2D3 on lung cancer cell in vitro. Using gain- and loss-of-function cell model, we demonstrated that lncBCAS1-4_1 functions as a negative feedback regulator that significantly blunts the therapeutic response to 1α,25(OH)₂D₃. While in vivo xenograft models showed that lncBCAS1-4_1 modulation alone had subtle effects on tumor initiation, its overexpression critically compromised the tumor-suppressive efficacy of 1α,25(OH)2D3 treatment. We uncover dual oncogenic mechanisms whereby lncBCAS1-4_1 not only accelerates EMT progression through its physical association with vimentin, but also transcriptionally upregulates key glycolytic regulators (HK2, LDHA, phosphorylated LDHA, and TKT). By simultaneously reprogramming cell plasticity and metabolic adaptability, lncBCAS1-4_1 emerges as a pivotal factor restricting the clinical utility of vitamin D monotherapy in lung cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316905 | GEO | 2026/04/30

REPOSITORIES: GEO

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Project description:Fibroblast growth factor 23 (FGF23) is produced and secreted by osteocytes and is essential for maintaining phosphate homeostasis. One of the main regulators of FGF23, 1,25-dihydroxyvitamin D (1,25(OH)2D3), is primarily synthesized in the kidney from 25-hydroxyvitamin D (25(OH)D) by 1α-hydroxylase (encoded by CYP27B1). Hitherto, it is unclear whether osteocytes can convert 25(OH)D and thereby allow for 1,25(OH)2D3 to induce FGF23 production and secretion locally. Here, we differentiated MC3T3-E1 cells towards osteocyte-like cells expressing and secreting FGF23. Treatment with 10-6 M 25(OH)D resulted in conversion of 25(OH)D to 150 pmol/L 1,25(OH)2D3 and increased FGF23 expression and secretion but the converted amount of 1,25(OH)2D3 was insufficient to trigger an FGF23 response, so the effect on FGF23 was most likely directly caused by 25(OH)D. Interestingly, combining phosphate with 25(OH)D resulted in a synergistic increase in FGF23 expression and secretion, likely due to activation of additional signaling pathways by phosphate. Blockage of the vitamin D receptor (VDR) only partially abolished the effects of 25(OH)D or 25(OH)D combined with phosphate on Fgf23, while completely inhibiting the upregulation of cytochrome P450 family 24 subfamily A member 1 (Cyp24a1), encoding for 24-hydroxylase. RNA sequencing and in silico analyses showed that this could potentially be mediated by the nuclear receptors Retinoic Acid Receptor b (RARB) and Estrogen Receptor 2 (ESR2). Taken together, we demonstrate that osteocytes are able to convert 25(OH)D to 1,25(OH)2D3, but this is insufficient for FGF23 activation, implicating a direct effect of 25(OH)D in the regulation of FGF23, which occurs at least partially independent from its cognate vitamin D receptor Moreover, phosphate and 25(OH)D synergistically increase expression and secretion of FGF23, which warrants investigating consequences in patients receiving a combination of vitamin D analogues and phosphate supplements. These observations help us to further understand the complex relations between, phosphate, vitamin D and FGF23.

Dataset Information

LncBCAS1-4_1, a Functional Homolog of CYP24A1, Attenuates the Anticancer Efficacy of 1,25(OH)₂D₃ in Lung Cancer via Glycolysis and EMT

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