SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair
Abstract Endometrial cancer (EC) stands as one of the most prevalent malignancies affecting the female genital tract, witnessing a rapid surge in incidence globally. Despite the well-established association of histone methyltransferase SMYD3 with the development and progression of various cancers, i...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
|
| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-023-00503-0 |
| _version_ | 1797355489447641088 |
|---|---|
| author | Yujia Huang Ming Tang Zhiyi Hu Bailian Cai Guofang Chen Lijun Jiang Yan Xia Pujun Guan Xiaoqi Li Zhiyong Mao Xiaoping Wan Wen Lu |
| author_facet | Yujia Huang Ming Tang Zhiyi Hu Bailian Cai Guofang Chen Lijun Jiang Yan Xia Pujun Guan Xiaoqi Li Zhiyong Mao Xiaoping Wan Wen Lu |
| author_sort | Yujia Huang |
| collection | DOAJ |
| description | Abstract Endometrial cancer (EC) stands as one of the most prevalent malignancies affecting the female genital tract, witnessing a rapid surge in incidence globally. Despite the well-established association of histone methyltransferase SMYD3 with the development and progression of various cancers, its specific oncogenic role in endometrial cancer remains unexplored. In the present study, we report that the expression level of SMYD3 is significantly upregulated in EC samples and associated with EC progression. Through meticulous in vivo and in vitro experiments, we reveal that depletion of SMYD3 curtails cell proliferation, migration, and invasion capabilities, leading to compromised non-homologous end joining repair (NHEJ) and heightened sensitivity of EC cells to radiation. Furthermore, our pathway enrichment analysis underscores the pivotal involvement of the DNA damage repair pathway in regulating EC progression. Mechanistically, in response to DNA damage, SMYD3 is recruited to these sites in a PARP1-dependent manner, specifically methylating LIG4. This methylation sets off a sequential assembly of the LIG4/XRCC4/XLF complex, actively participating in the NHEJ pathway and thereby fostering EC progression. Notably, our findings highlight the promise of SMYD3 as a crucial player in NHEJ repair and its direct correlation with EC progression. Intriguingly, pharmacological intervention targeting SMYD3 with its specific inhibitor, BCI-121, emerges as a potent strategy, markedly suppressing the tumorigenicity of EC cells and significantly enhancing the efficacy of radiotherapy. Collectively, our comprehensive data position SMYD3 as a central factor in NHEJ repair and underscore its potential as a promising pharmacological target for endometrial cancer therapy, validated through both in vitro and in vivo systems. |
| first_indexed | 2024-03-08T14:11:54Z |
| format | Article |
| id | doaj.art-253bdfc5ebc84132a9134c312aabf5d0 |
| institution | Directory Open Access Journal |
| issn | 2157-9024 |
| language | English |
| last_indexed | 2024-03-08T14:11:54Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj.art-253bdfc5ebc84132a9134c312aabf5d02024-01-14T12:36:59ZengNature Publishing GroupOncogenesis2157-90242024-01-0113111310.1038/s41389-023-00503-0SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repairYujia Huang0Ming Tang1Zhiyi Hu2Bailian Cai3Guofang Chen4Lijun Jiang5Yan Xia6Pujun Guan7Xiaoqi Li8Zhiyong Mao9Xiaoping Wan10Wen Lu11Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityDepartment of Radiology, West China Hospital, Sichuan UniversityDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji UniversityAbstract Endometrial cancer (EC) stands as one of the most prevalent malignancies affecting the female genital tract, witnessing a rapid surge in incidence globally. Despite the well-established association of histone methyltransferase SMYD3 with the development and progression of various cancers, its specific oncogenic role in endometrial cancer remains unexplored. In the present study, we report that the expression level of SMYD3 is significantly upregulated in EC samples and associated with EC progression. Through meticulous in vivo and in vitro experiments, we reveal that depletion of SMYD3 curtails cell proliferation, migration, and invasion capabilities, leading to compromised non-homologous end joining repair (NHEJ) and heightened sensitivity of EC cells to radiation. Furthermore, our pathway enrichment analysis underscores the pivotal involvement of the DNA damage repair pathway in regulating EC progression. Mechanistically, in response to DNA damage, SMYD3 is recruited to these sites in a PARP1-dependent manner, specifically methylating LIG4. This methylation sets off a sequential assembly of the LIG4/XRCC4/XLF complex, actively participating in the NHEJ pathway and thereby fostering EC progression. Notably, our findings highlight the promise of SMYD3 as a crucial player in NHEJ repair and its direct correlation with EC progression. Intriguingly, pharmacological intervention targeting SMYD3 with its specific inhibitor, BCI-121, emerges as a potent strategy, markedly suppressing the tumorigenicity of EC cells and significantly enhancing the efficacy of radiotherapy. Collectively, our comprehensive data position SMYD3 as a central factor in NHEJ repair and underscore its potential as a promising pharmacological target for endometrial cancer therapy, validated through both in vitro and in vivo systems.https://doi.org/10.1038/s41389-023-00503-0 |
| spellingShingle | Yujia Huang Ming Tang Zhiyi Hu Bailian Cai Guofang Chen Lijun Jiang Yan Xia Pujun Guan Xiaoqi Li Zhiyong Mao Xiaoping Wan Wen Lu SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair Oncogenesis |
| title | SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair |
| title_full | SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair |
| title_fullStr | SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair |
| title_full_unstemmed | SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair |
| title_short | SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair |
| title_sort | smyd3 promotes endometrial cancer through epigenetic regulation of lig4 xrcc4 xlf complex in non homologous end joining repair |
| url | https://doi.org/10.1038/s41389-023-00503-0 |
| work_keys_str_mv | AT yujiahuang smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT mingtang smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT zhiyihu smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT bailiancai smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT guofangchen smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT lijunjiang smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT yanxia smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT pujunguan smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT xiaoqili smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT zhiyongmao smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT xiaopingwan smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair AT wenlu smyd3promotesendometrialcancerthroughepigeneticregulationoflig4xrcc4xlfcomplexinnonhomologousendjoiningrepair |