Transcriptional regulation of Dyskerinviacanonical WNT signaling modulates sphingolipid biosynthesis and drives colorectal cancer

Targeting EGFR has been effective in RAS/RAF wild-type colorectal cancer (CRC) patients. However, residual tumor relapses, necessitating the importance of biomarker-guided novel therapeutics. We show elevated DKC1 in ∼88% of CRC patients with poor recurrence-free survival. Clinically, DKC1- positive patients exhibit similarity with CMS2 class, the canonical subtype with active WNT signaling. We show functional significance of DKC1 in cell proliferation, stemness, DNA repair, and survival. Further, mice bearing DKC1 knockdown xenografts show ∼81% reduction in tumor burden. Mechanistically, WNT/β-catenin signaling orchestrates DKC1 expression, then, DKC1/SOX2 complex regulates SGPP2 , modulating sphingolipids metabolism. Downregulation of DKC1 in CRC lead to reduced SGPP2 levels leading to dysregulation of sphingolipid biosynthesis. Of note, DKC1 -high CRC patients show accumulation of ceramides, namely C23 and C24, signifying their utility in diagnosis. Collectively, we delineate the mechanistic circuitry involved in DKC1-mediated CRC progression, propose ceramides as biomarker, and underscore WNT-based therapeutics for DKC1-positive patients.