Umar K. Khan, Ayush Goel, Shivansh Nigam, Nazia Chaudhary, Ayush Praveen, Anjan Roy, Fabeha Fatima, Dilpreet K. Sawhney, Afiya Dalwai, Akshay Shendre, Shannon Carskadon, A. K. Bajpai, Abhimanyu Kapoor, Anjali Tewari, Abhijit Chandra, A. Saklani, Sorab N. Dalal, Nallasivam Palanisamy, Bushra Ateeq
DKC1, a key coordinator of RNA modification and telomerase activity, has been implicated in colorectal cancer (CRC), yet its role in disease pathogenesis remains incompletely understood. We show that DKC1 drives CRC by promoting cell cycle progression, suppressing apoptosis, conferring stemness and drug resistance. Elevated DKC1 in CRC associates with poor prognosis and WNT-enriched Consensus Molecular Subtype 2 gene signature. Mechanistically, canonical WNT-signaling forms a feedback loop with DKC1, driving its expression and oncogenic activity. Comprehensive transcriptomic and lipidomic analyses reveal perturbed sphingolipid metabolism and abundance of specific very-long-chain fatty acid ceramides. Further, a regulatory axis involving DKC1 and SOX2 drives the expression of SGPP2, a critical sphingolipid metabolism mediator. Importantly, DKC1-mediated sphingolipid dysregulation promotes first-line chemoresistance, and FOLFOX-resistant patient-derived organoids effectively respond to DKC1 and WNT signaling inhibitors. Conclusively, we identify the DKC1/WNT axis as a therapeutic target in therapy-resistant CRC and underscore complex sphingolipids as promising plasma-based biomarkers. Dyskerin pseudouridine synthase 1 (DKC1) has shown multifaceted roles in cancer. Here, the authors find that the crosstalk between WNT signaling and DKC1 dysregulates sphingolipid biosynthesis and drives chemoresistance in colorectal cancer experimental models.