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

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 seq...

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Main Authors: Yueshuo Li, Chenxing Yang, Longlong Xie, Feng Shi, Min Tang, Xiangjian Luo, Na Liu, Xudong Hu, Yongwei Zhu, Ann M. Bode, Qiang Gao, Jian Zhou, Jia Fan, Xuejun Li, Ya Cao
Format: Article
Language:English
Published: Nature Publishing Group 2024-01-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-024-06419-w
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author Yueshuo Li
Chenxing Yang
Longlong Xie
Feng Shi
Min Tang
Xiangjian Luo
Na Liu
Xudong Hu
Yongwei Zhu
Ann M. Bode
Qiang Gao
Jian Zhou
Jia Fan
Xuejun Li
Ya Cao
author_facet Yueshuo Li
Chenxing Yang
Longlong Xie
Feng Shi
Min Tang
Xiangjian Luo
Na Liu
Xudong Hu
Yongwei Zhu
Ann M. Bode
Qiang Gao
Jian Zhou
Jia Fan
Xuejun Li
Ya Cao
author_sort Yueshuo Li
collection DOAJ
description 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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spelling doaj.art-f0d88082449b4f8b878e1387a80ca5d12024-03-05T20:30:35ZengNature Publishing GroupCell Death and Disease2041-48892024-01-0115111510.1038/s41419-024-06419-wCYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinomaYueshuo Li0Chenxing Yang1Longlong Xie2Feng Shi3Min Tang4Xiangjian Luo5Na Liu6Xudong Hu7Yongwei Zhu8Ann M. Bode9Qiang Gao10Jian Zhou11Jia Fan12Xuejun Li13Ya Cao14Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityKey Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityChildren’s Hospital, Xiangya School of Medicine, Central South UniversityKey Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityKey Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityKey Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityKey Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityKey Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityDepartment of Neurosurgery, National Clinical Research Center for Geriatric Disorders/ Xiangya Hospital, Central South UniversityThe Hormel Institute, University of MinnesotaKey Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan UniversityKey Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan UniversityKey Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityKey Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Neurosurgery, Xiangya Hospital, Central South UniversityAbstract 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.https://doi.org/10.1038/s41419-024-06419-w
spellingShingle Yueshuo Li
Chenxing Yang
Longlong Xie
Feng Shi
Min Tang
Xiangjian Luo
Na Liu
Xudong Hu
Yongwei Zhu
Ann M. Bode
Qiang Gao
Jian Zhou
Jia Fan
Xuejun Li
Ya Cao
CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma
Cell Death and Disease
title CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma
title_full CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma
title_fullStr CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma
title_full_unstemmed CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma
title_short CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma
title_sort cyld induces high oxidative stress and dna damage through class i hdacs to promote radiosensitivity in nasopharyngeal carcinoma
url https://doi.org/10.1038/s41419-024-06419-w
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