PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer
Abstract Background Aberrant epigenetic remodeling events contribute to progression and metastasis of breast cancer (Bca). The specific mechanims that epigenetic factors rely on to mediate tumor aggressiveness remain unclear. We aimed to elucidate the roles of epigenetic protein PHF6 in breast tumor...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04031-8 |
| _version_ | 1797859851549802496 |
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| author | Sheng Gao Wensheng Zhang Jingjing Ma Xiaojian Ni |
| author_facet | Sheng Gao Wensheng Zhang Jingjing Ma Xiaojian Ni |
| author_sort | Sheng Gao |
| collection | DOAJ |
| description | Abstract Background Aberrant epigenetic remodeling events contribute to progression and metastasis of breast cancer (Bca). The specific mechanims that epigenetic factors rely on to mediate tumor aggressiveness remain unclear. We aimed to elucidate the roles of epigenetic protein PHF6 in breast tumorigenesis. Methods Published datasets and tissue samples with PHF6 staining were used to investigate the clinical relevance of PHF6 in Bca. CCK-8, clony formation assays were used to assess cell growth capacity. Cell migration and invasion abilities were measured by Transwell assay. The gene mRNA and protein levels were measured by quantitative real-time PCR and western blot. Chromatin immunoprecipitation (ChIP)-qPCR assays were used to investigate transcriptional relationships among genes. The Co-immunoprecipitation (Co-IP) assay was used to validate interactions between proteins. The CRISPR/Cas9 editing technology was used to construct double HIF knockout (HIF-DKO) cells. The subcutaneous xenograft model and orthotopic implantation tumor model were used to asess in vivo tumor growth. Results In this study, we utilized MTT assay to screen that PHF6 is required for Bca growth. PHF6 promotes Bca proliferation and migration. By analyzing The Cancer Genome Atlas breast cancer (TCGA-Bca) cohort, we found that PHF6 was significantly higher in tumor versus normal tissues. Mechanistically, PHF6 physically interacts with HIF-1α and HIF-2α to potentiate HIF-driven transcriptional events to initiate breast tumorigenesis. HIF-DKO abolished PHF6-mediated breast tumor growth, and PHF6 deficiency in turn impaired HIF transcriptional effects. Besides, hypoxia could also rely on YAP activation, but not HIF, to sustain PHF6 expressions in Bca cells. In addition, PHF6 recuits BPTF to mediate epigenetic remodeling to augment HIF transcriptional activity. Targeting PHF6 or BPTF inhibitor (AU1) is effective in mice models. Lastly, PHF6 correlated with HIF target gene expression in human breast tumors, which is an independent prognostic regulator. Conclusions Collectively, this study identified PHF6 as a prognostic epigenetic regulator for Bca, functioning as a HIF coactivator. The fundamental mechanisms underlying YAP/PHF6/HIF axis in breast tumors endowed novel epigenegtic targets for Bca treatment. |
| first_indexed | 2024-04-09T21:37:19Z |
| format | Article |
| id | doaj.art-d9ec0570e5dd4d83b4eeabcc339e4d4b |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-09T21:37:19Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-d9ec0570e5dd4d83b4eeabcc339e4d4b2023-03-26T11:16:47ZengBMCJournal of Translational Medicine1479-58762023-03-0121111810.1186/s12967-023-04031-8PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancerSheng Gao0Wensheng Zhang1Jingjing Ma2Xiaojian Ni3Department of Breast, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care HospitalState Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Key Laboratory of Reproduction Regulation of NPFPC and Collaborative Innovation Center for Genetics and Development, Fudan UniversityDepartment of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityAbstract Background Aberrant epigenetic remodeling events contribute to progression and metastasis of breast cancer (Bca). The specific mechanims that epigenetic factors rely on to mediate tumor aggressiveness remain unclear. We aimed to elucidate the roles of epigenetic protein PHF6 in breast tumorigenesis. Methods Published datasets and tissue samples with PHF6 staining were used to investigate the clinical relevance of PHF6 in Bca. CCK-8, clony formation assays were used to assess cell growth capacity. Cell migration and invasion abilities were measured by Transwell assay. The gene mRNA and protein levels were measured by quantitative real-time PCR and western blot. Chromatin immunoprecipitation (ChIP)-qPCR assays were used to investigate transcriptional relationships among genes. The Co-immunoprecipitation (Co-IP) assay was used to validate interactions between proteins. The CRISPR/Cas9 editing technology was used to construct double HIF knockout (HIF-DKO) cells. The subcutaneous xenograft model and orthotopic implantation tumor model were used to asess in vivo tumor growth. Results In this study, we utilized MTT assay to screen that PHF6 is required for Bca growth. PHF6 promotes Bca proliferation and migration. By analyzing The Cancer Genome Atlas breast cancer (TCGA-Bca) cohort, we found that PHF6 was significantly higher in tumor versus normal tissues. Mechanistically, PHF6 physically interacts with HIF-1α and HIF-2α to potentiate HIF-driven transcriptional events to initiate breast tumorigenesis. HIF-DKO abolished PHF6-mediated breast tumor growth, and PHF6 deficiency in turn impaired HIF transcriptional effects. Besides, hypoxia could also rely on YAP activation, but not HIF, to sustain PHF6 expressions in Bca cells. In addition, PHF6 recuits BPTF to mediate epigenetic remodeling to augment HIF transcriptional activity. Targeting PHF6 or BPTF inhibitor (AU1) is effective in mice models. Lastly, PHF6 correlated with HIF target gene expression in human breast tumors, which is an independent prognostic regulator. Conclusions Collectively, this study identified PHF6 as a prognostic epigenetic regulator for Bca, functioning as a HIF coactivator. The fundamental mechanisms underlying YAP/PHF6/HIF axis in breast tumors endowed novel epigenegtic targets for Bca treatment.https://doi.org/10.1186/s12967-023-04031-8PHF6BPTFHIFEpigenetic remodelingBreast cancer |
| spellingShingle | Sheng Gao Wensheng Zhang Jingjing Ma Xiaojian Ni PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer Journal of Translational Medicine PHF6 BPTF HIF Epigenetic remodeling Breast cancer |
| title | PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer |
| title_full | PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer |
| title_fullStr | PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer |
| title_full_unstemmed | PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer |
| title_short | PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer |
| title_sort | phf6 recruits bptf to promote hif dependent pathway and progression in yap high breast cancer |
| topic | PHF6 BPTF HIF Epigenetic remodeling Breast cancer |
| url | https://doi.org/10.1186/s12967-023-04031-8 |
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