Aberrant Accumulation of Cyclin D1 Rewires Glutamine Metabolism and Generates a Metabolic Vulnerability in Squamous Cell Carcinoma.

Authors

Shuyuan Zhang, Polly J Phillips-Mason, Bartosz Mucha, Marganit Farago, Guofang Zhang, Cecilia Martin, Andres J Klein-Szanto, Hiroshi Nakagawa, Anil K Rustgi, Kwok-Kin Wong, Brian S Henick, J Alan Diehl

Published in

Cancer research. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Excessive cyclin D1 accumulation is a frequent oncogenic event in head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). Although classically associated with enhanced proliferation and genomic instability, we revealed that cyclin D1 dysregulation induces metabolic rewiring that leads to unexpected metabolic dependencies. Sustained nuclear retention of cyclin D1 drove metabolic reprogramming through activation of CDK4/6 and downregulation of mitochondrial isocitrate dehydrogenase 3 (IDH3), reducing α-ketoglutarate and NADH production. This metabolic alteration increased glutamine dependence and elevated autophagic flux, and co-targeting autophagy and glutamine metabolism suppressed the growth of squamous cell carcinoma models in vitro and in vivo. Together, these findings highlight a therapeutic strategy for HNSCC and ESCC that leverages metabolic reprogramming induced by dysregulated cyclin D1/CDK4 activity, with potential applicability to patients with tumors refractory to conventional therapies.

PMID:
42831554
Bibliographic data and abstract were imported from PubMed on 05 Oct 2026.

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