The role of 7-dehydrocholesterol in inducing ER stress and apoptosis of head and neck squamous cell carcinoma

Bok-Soon Lee, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA; Department of Otolaryngology, Ajou University School of Medicine, Suwon, South Korea.
Yea-In Park, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Hengtian Liu, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Sang Gyu Kim, Department of Otolaryngology, Ajou University School of Medicine, Suwon, South Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, South Korea.
Hyo Jeong Kim, Department of Otolaryngology, Ajou University School of Medicine, Suwon, South Korea.
Ji-Hye Choi, Department of Physiology, Ajou University School of Medicine, Suwon, South Korea.
Si Hyun Rho, Department of Otolaryngology, Ajou University School of Medicine, Suwon, South Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, South Korea.
Joselyn Padilla, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Jin Roh, Department of Pathology, Ajou University School of Medicine, Suwon, South Korea.
Hyun Goo Woo, Department of Physiology, Ajou University School of Medicine, Suwon, South Korea.
Hae Jin Seo, Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul, South Korea.
Man Ho Choi, Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul, South Korea.
Yu-Jin Jeong, Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
Evan C. Lien, Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
Syed Hassan Mehdi, Hematology Oncology Division, Department of Internal Medicine, The University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Dongjoon Lee, Hematology Oncology Division, Department of Internal Medicine, The University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Donghoon Yoon, Hematology Oncology Division, Department of Internal Medicine, The University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Chul-Ho Kim, Department of Otolaryngology, Ajou University School of Medicine, Suwon, South Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, South Korea. Electronic address: ostium@ajou.ac.kr.
Jiyoung Lee, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA; GW Cancer Center, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA. Electronic address: jiyounglee@gwu.edu.

Document Type

Journal Article

Publication Date

9-28-2025

Journal

Cancer letters

Volume

628

DOI

10.1016/j.canlet.2025.217842

Keywords

7-Dehydrocholesterol; Cholesterol metabolism; DHCR24; DHCR7; ER stress; Head and neck cancer

Abstract

Alterations of metabolic pathways that sustain cancer cell survival often offer promising therapeutic avenues. Here, we show that enhanced de novo cholesterol biosynthesis is crucial for the survival of head and neck squamous cell carcinoma (HNSCC). Transcriptomic analysis of HNSCC tissues identified profound dysregulation in steroid and cholesterol metabolism compared to normal tissues. Inhibition of two key enzymes, DHCR7 and DHCR24, which mediate cholesterol biosynthesis, induced apoptosis in HNSCC cells, even when cholesterol levels were restored. Metabolomic profiling revealed the accumulation of 7-dehydrocholesterol (7-DHC) upon DHCR7 or DHCR24 inhibition, triggering endoplasmic reticulum (ER) stress and promoting further cell death. These findings suggest that HNSCC cells adapt to ER stress by modulating 7-DHC levels through enhancing DHCR7 and DHCR24 levels, highlighting a metabolic vulnerability in HNSCC and demonstrating a direct link between cholesterol metabolism and ER stress in cancer cell viability.

Department

Biochemistry and Molecular Medicine

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