G9a deficiency activates TMEM27 to promote ferroptosis and enhances radiosensitivity in head and neck squamous cell carcinoma

Cell Death Discov. 2025 Nov 10;11(1):517. doi: 10.1038/s41420-025-02805-1.

Junli Hu ¹ ² ³ ⁴, Yuanzheng Qiu ¹ ³ ⁴ ⁵, Wenhui Yuan ¹ ³ ⁴, Guo Li ¹ ³ ⁴ ⁵, Donghai Huang ¹ ³ ⁴ ⁵, Xin Zhang ¹ ³ ⁴ ⁵, Yong Liu ¹ ³ ⁴ ⁵, Shanhong Lu ⁶ ⁷ ⁸ ⁹, Chao Liu ¹⁰ ¹¹ ¹² ¹³

Affiliations

1 Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.
2 Department of Otolaryngology Head and Neck Surgery, Yantian District People's Hospital, Shenzhen, Guangdong, China.
3 Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.
4 Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China.
5 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
6 Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China. [email protected].
7 Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China. [email protected].
8 Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China. [email protected].
9 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. [email protected].
10 Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China. [email protected].
11 Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China. [email protected].
12 Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China. [email protected].
13 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. [email protected].

PMID: 41213903 DOI: 10.1038/s41420-025-02805-1

Abstract

Epigenetic regulation, which modulates gene expression without altering the DNA sequence, plays a critical role in adaptive responses to environmental stressors, including irradiation. In this study, we investigated the role of histone H3K9 methylation in radiotherapy for head and neck squamous cell carcinoma (HNSCC). We identified G9a, a key lysine methyltransferase, as a critical regulator of H3K9me2 methylation in HNSCC radiotherapy. Inhibition of G9a using the small molecule inhibitor BRD4770 significantly enhanced radiosensitivity in HNSCC cells. Ferroptosis, a recently discovered form of iron-dependent cell death driven by lipid peroxidation, was found to play a pivotal role in radiotherapy-induced cell death and tumor suppression. RNA Sequencing and KEGG pathway analysis revealed that G9a knockout increased radiosensitivity primarily by inducing Ferroptosis. Further screening identified TMEM27 as a downstream target gene, and ChIP-qPCR confirmed that G9a binds to the H3K9me2 site of TMEM27, regulating its transcription. Importantly, we demonstrated that G9a-mediated expression of TMEM27 depends on its Histone Methyltransferase activity. In summary, this study reveals that G9a deficiency enhances radiosensitivity in HNSCC by activating TMEM27 to promote Ferroptosis, providing a novel therapeutic strategy for overcoming radiotherapy resistance.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-16705

BRD4770

99.79%, G9a Inhibitor

Histone Methyltransferase

Cancer

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