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

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.