DKC1 promotes colorectal cancer progression and therapy resistance by dysregulating sphingolipid biosynthesis
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.
Authors
- Nazia Chaudhary (ORCID: https://orcid.org/0009-0008-8993-5975)
- Abhimanyu Kapoor
- Abhijit Chandra (ORCID: https://orcid.org/0000-0002-3940-7428)
- Shivansh Nigam (ORCID: https://orcid.org/0000-0003-1148-9801)
- Nallasivam Palanisamy (ORCID: https://orcid.org/0000-0002-0633-9772)
- Ayush Praveen (ORCID: https://orcid.org/0009-0001-1086-3948)
- Anjali Tewari (ORCID: https://orcid.org/0000-0002-2093-3225)
- A. Saklani
- Bushra Ateeq
- Ayush Goel (ORCID: https://orcid.org/0000-0001-6996-6418)
- A. K. Bajpai (ORCID: https://orcid.org/0000-0002-5645-2466)
- Akshay Shendre
- Shannon Carskadon (ORCID: https://orcid.org/0000-0002-6950-0308)
- Afiya Dalwai
- Dilpreet K. Sawhney (ORCID: https://orcid.org/0009-0007-9224-2988)
- Fabeha Fatima (ORCID: https://orcid.org/0009-0006-8049-1488)
- Sorab N. Dalal (ORCID: https://orcid.org/0000-0001-6883-7550)
- Umar K. Khan (ORCID: https://orcid.org/0000-0003-1199-2511)
- Anjan Roy (ORCID: https://orcid.org/0009-0003-9966-1369)
Institutions
- Henry Ford Health System (US)
- Homi Bhabha National Institute (IN)
- Chhatrapati Shahu Ji Maharaj University (IN)
- Tata Memorial Hospital (IN)
- King George's Medical University (IN)
- Advanced Centre for Treatment, Research and Education in Cancer (IN)
- Indian Institute of Technology Kanpur (IN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-18
- DOI
- https://doi.org/10.1038/s41467-026-72800-2
- Primary Topic
- Sphingolipid Metabolism and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00