<br>CYLD 通过 I 类 HDAC 诱导高氧化应激和 DNA 损伤，促进鼻咽癌的放射敏感性,Cell Death & Disease

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CYLD 通过 I 类 HDAC 诱导高氧化应激和 DNA 损伤，促进鼻咽癌的放射敏感性
Cell Death & Disease ( IF 8.1 ) Pub Date : 2024-01-29 , 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 _{1,

2,

4} , Ya Cao _{1,

3,

6,

9,

10,

11}

Affiliation

Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410078, China.
Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders/ Xiangya Hospital, Central South University, Changsha, 410078, China.
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.
Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Children's Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, China.
Molecular Imaging Research Center of Central South University, Changsha, 410008, Hunan, China.
The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai, 200000, China.
Department of Radiology, National Clinical Research Center for Geriatric Disorders/ Xiangya Hospital, Central South University, Changsha, 410078, China.
Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha, 410078, China.
National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha, 410078, China.

圆柱瘤病（CYLD）是一种抑癌分子，其异常表达在肿瘤发生和治疗中起着重要作用。在这项工作中，我们发现 CYLD 通过其 N 末端结构域与 I 类组蛋白脱乙酰酶（HDAC1 和 HDAC2）结合并抑制 HDAC1 活性。RNA 测序显示 CYLD-HDAC 轴通过 Nrf2 及其靶基因调节细胞抗氧化反应。然后我们揭示了 I 类 HDAC 介导 CYLD 低表达肿瘤氧化还原异常的机制。HDAC 是 DNA 损伤信号传导的核心参与者。我们进一步证实 CYLD 通过抑制 I 类 HDAC 来调节辐射诱导的 DNA 损伤和修复反应。此外，CYLD 通过 I 类 HDAC 介导鼻咽癌细胞放射敏感性。因此，我们确定了 CYLD-HDAC 轴在放疗中的作用，西达本胺阻断 HDAC 可以增加癌细胞和肿瘤对体外和体内放疗的敏感性。此外，ChIP 和荧光素酶报告基因分析显示，CYLD 可受锌指蛋白 202 （ZNF202）的转录调控。我们的研究结果为 CYLD 在肿瘤中的功能提供了新的见解，并揭示了 CYLD-HDAC 轴在放射敏感性中的重要作用，这为肿瘤放疗提供了新的分子靶点和治疗策略。

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

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.

更新日期：2024-01-31

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