SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair
Abstract Background Cisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy. Results We performed whole exome sequencing (WES) of 15...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-06-01
|
| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-023-01054-y |
| _version_ | 1797801277349953536 |
|---|---|
| author | Xin Wang Chen Cao Xiangyu Tan Xueyao Liao Xiaofang Du Xueqian Wang Ting Liu Danni Gong Zheng Hu Xun Tian |
| author_facet | Xin Wang Chen Cao Xiangyu Tan Xueyao Liao Xiaofang Du Xueqian Wang Ting Liu Danni Gong Zheng Hu Xun Tian |
| author_sort | Xin Wang |
| collection | DOAJ |
| description | Abstract Background Cisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy. Results We performed whole exome sequencing (WES) of 156 cervical cancer tissues to assess genomic features related to platinum-based chemoresistance. By using WES, we identified a frequently mutated locus SETD8 (7%), which was associated with drug sensitivity. Cell functional assays, in vivo xenografts tumor growth experiments, and survival analysis were used to investigate the functional significance and mechanism of chemosensitization after SETD8 downregulation. Knockdown of SETD8 increased the responsiveness of cervical cancer cells to cisplatin treatment. The mechanism is exerted by reduced binding of 53BP1 to DNA breaks and inhibition of the non-homologous end joining (NHEJ) repair pathway. In addition, SETD8 expression was positively correlated with resistance to cisplatin and negatively associated with the prognosis of cervical cancer patients. Further, UNC0379 as a small molecule inhibitor of SETD8 was found to enhance cisplatin sensitivity both in vitro and in vivo. Conclusions SETD8 was a promising therapeutic target to ameliorate cisplatin resistance and improve the efficacy of chemotherapy. |
| first_indexed | 2024-03-13T04:48:00Z |
| format | Article |
| id | doaj.art-f1b2f84a100043fbb949cdb3a785dcd2 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-03-13T04:48:00Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-f1b2f84a100043fbb949cdb3a785dcd22023-06-18T11:25:59ZengBMCCell & Bioscience2045-37012023-06-0113111510.1186/s13578-023-01054-ySETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repairXin Wang0Chen Cao1Xiangyu Tan2Xueyao Liao3Xiaofang Du4Xueqian Wang5Ting Liu6Danni Gong7Zheng Hu8Xun Tian9Department of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gynecologic Oncology, Women and Children’s Hospital Affiliated to Zhongnan Hospital of Wuhan UniversityDepartment of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Cisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy. Results We performed whole exome sequencing (WES) of 156 cervical cancer tissues to assess genomic features related to platinum-based chemoresistance. By using WES, we identified a frequently mutated locus SETD8 (7%), which was associated with drug sensitivity. Cell functional assays, in vivo xenografts tumor growth experiments, and survival analysis were used to investigate the functional significance and mechanism of chemosensitization after SETD8 downregulation. Knockdown of SETD8 increased the responsiveness of cervical cancer cells to cisplatin treatment. The mechanism is exerted by reduced binding of 53BP1 to DNA breaks and inhibition of the non-homologous end joining (NHEJ) repair pathway. In addition, SETD8 expression was positively correlated with resistance to cisplatin and negatively associated with the prognosis of cervical cancer patients. Further, UNC0379 as a small molecule inhibitor of SETD8 was found to enhance cisplatin sensitivity both in vitro and in vivo. Conclusions SETD8 was a promising therapeutic target to ameliorate cisplatin resistance and improve the efficacy of chemotherapy.https://doi.org/10.1186/s13578-023-01054-yCisplatin sensitivitySETD8Cervical cancerDNA repairWhole exome sequencing |
| spellingShingle | Xin Wang Chen Cao Xiangyu Tan Xueyao Liao Xiaofang Du Xueqian Wang Ting Liu Danni Gong Zheng Hu Xun Tian SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair Cell & Bioscience Cisplatin sensitivity SETD8 Cervical cancer DNA repair Whole exome sequencing |
| title | SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair |
| title_full | SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair |
| title_fullStr | SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair |
| title_full_unstemmed | SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair |
| title_short | SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair |
| title_sort | setd8 a frequently mutated gene in cervical cancer enhances cisplatin sensitivity by impairing dna repair |
| topic | Cisplatin sensitivity SETD8 Cervical cancer DNA repair Whole exome sequencing |
| url | https://doi.org/10.1186/s13578-023-01054-y |
| work_keys_str_mv | AT xinwang setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT chencao setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT xiangyutan setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT xueyaoliao setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT xiaofangdu setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT xueqianwang setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT tingliu setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT dannigong setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT zhenghu setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair AT xuntian setd8afrequentlymutatedgeneincervicalcancerenhancescisplatinsensitivitybyimpairingdnarepair |