lncBCAS1-4_1, a Functional Homolog of CYP24A1, Attenuates the Anticancer Efficacy of 1,25(OH)₂D₃ in Lung Cancer via Glycolysis and EMT

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.