2. Academic Validation
  3. CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma

CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma

  • Cell Death Dis. 2024 Jan 29;15(1):95. doi: 10.1038/s41419-024-06419-w.
Yueshuo Li 1 2 3 4,  Chenxing Yang 1 3,  Longlong Xie 5,  Feng Shi 1 3,  Min Tang 1 3 6,  Xiangjian Luo 1 3 6,  Na Liu 1 3,  Xudong Hu 1 3,  Yongwei Zhu 2 4,  Ann M Bode 7,  Qiang Gao 8,  Jian Zhou 8,  Jia Fan 8,  Xuejun Li 9 10 11,  Ya Cao 12 13 14 15 16 17
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410078, China.
  • 2 Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders/ Xiangya Hospital, Central South University, Changsha, 410078, China.
  • 3 Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China.
  • 4 Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 5 Children's Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, China.
  • 6 Molecular Imaging Research Center of Central South University, Changsha, 410008, Hunan, China.
  • 7 The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
  • 8 Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, 200000, China.
  • 9 Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410078, China. [email protected].
  • 10 Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders/ Xiangya Hospital, Central South University, Changsha, 410078, China. [email protected].
  • 11 Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
  • 12 Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410078, China. [email protected].
  • 13 Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China. [email protected].
  • 14 Molecular Imaging Research Center of Central South University, Changsha, 410008, Hunan, China. [email protected].
  • 15 Department of Radiology, National Clinical Research Center for Geriatric Disorders/ Xiangya Hospital, Central South University, Changsha, 410078, China. [email protected].
  • 16 Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha, 410078, China. [email protected].
  • 17 National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha, 410078, China. [email protected].
PMID: 38287022 DOI: 10.1038/s41419-024-06419-w
Abstract

Abnormal expression of Cylindromatosis (CYLD), a tumor suppressor molecule, plays an important role in tumor development and treatment. In this work, we found that CYLD binds to class I histone deacetylases (HDAC1 and HDAC2) through its N-terminal domain and inhibits HDAC1 activity. RNA sequencing showed that CYLD-HDAC axis regulates cellular antioxidant response via Nrf2 and its target genes. Then we revealed a mechanism that class I HDACs mediate redox abnormalities in CYLD low-expressing tumors. HDACs are central players in the DNA damage signaling. We further confirmed that CYLD regulates radiation-induced DNA damage and repair response through inhibiting class I HDACs. Furthermore, CYLD mediates nasopharyngeal carcinoma cell radiosensitivity through class I HDACs. Thus, we identified the function of the CYLD-HDAC axis in radiotherapy and blocking HDACs by Chidamide can increase the sensitivity of Cancer cells and tumors to radiation therapy both in vitro and in vivo. In addition, ChIP and luciferase reporter assays revealed that CYLD could be transcriptionally regulated by zinc finger protein 202 (ZNF202). Our findings offer novel insight into the function of CYLD in tumor and uncover important roles for CYLD-HDAC axis in radiosensitivity, which provide new molecular target and therapeutic strategy for tumor radiotherapy.

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Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100508
    ≥98.0%, HDAC activator
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