The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells
The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency le...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-06-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.664375/full |
| _version_ | 1818571727615033344 |
|---|---|
| author | Ziyu Zhang Baoyu Chen Yuwen Zhu Tianyi Zhang Xiaoling Zhang Xiaoling Zhang Yibiao Yuan Yong Xu Yong Xu |
| author_facet | Ziyu Zhang Baoyu Chen Yuwen Zhu Tianyi Zhang Xiaoling Zhang Xiaoling Zhang Yibiao Yuan Yong Xu Yong Xu |
| author_sort | Ziyu Zhang |
| collection | DOAJ |
| description | The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-β-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-β signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-β-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-β regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers. |
| first_indexed | 2024-12-14T18:48:10Z |
| format | Article |
| id | doaj.art-51a61b1f0301413faa16ecb783c19803 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-14T18:48:10Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-51a61b1f0301413faa16ecb783c198032022-12-21T22:51:20ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-06-01910.3389/fcell.2021.664375664375The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer CellsZiyu Zhang0Baoyu Chen1Yuwen Zhu2Tianyi Zhang3Xiaoling Zhang4Xiaoling Zhang5Yibiao Yuan6Yong Xu7Yong Xu8Department of Pathology, Jiangxi Maternal and Child Health Hospital, Nanchang, ChinaKey Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaSchool of Medicine, Nanchang University, Nanchang, ChinaDepartment of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, ChinaKey Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaInstitute of Biomedical Research, Liaocheng University, Liaocheng, ChinaThe small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-β-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-β signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-β-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-β regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers.https://www.frontiersin.org/articles/10.3389/fcell.2021.664375/fulltranscriptional regulationepigeneticshistone demethylasebreast cancer cellhistone methylation |
| spellingShingle | Ziyu Zhang Baoyu Chen Yuwen Zhu Tianyi Zhang Xiaoling Zhang Xiaoling Zhang Yibiao Yuan Yong Xu Yong Xu The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells Frontiers in Cell and Developmental Biology transcriptional regulation epigenetics histone demethylase breast cancer cell histone methylation |
| title | The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells |
| title_full | The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells |
| title_fullStr | The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells |
| title_full_unstemmed | The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells |
| title_short | The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells |
| title_sort | jumonji domain containing histone demethylase homolog 1d lysine demethylase 7a jhdm1d kdm7a is an epigenetic activator of rhoj transcription in breast cancer cells |
| topic | transcriptional regulation epigenetics histone demethylase breast cancer cell histone methylation |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.664375/full |
| work_keys_str_mv | AT ziyuzhang thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT baoyuchen thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT yuwenzhu thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT tianyizhang thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT xiaolingzhang thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT xiaolingzhang thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT yibiaoyuan thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT yongxu thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT yongxu thejumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT ziyuzhang jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT baoyuchen jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT yuwenzhu jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT tianyizhang jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT xiaolingzhang jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT xiaolingzhang jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT yibiaoyuan jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT yongxu jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells AT yongxu jumonjidomaincontaininghistonedemethylasehomolog1dlysinedemethylase7ajhdm1dkdm7aisanepigeneticactivatorofrhojtranscriptioninbreastcancercells |