Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer
Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL...
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eLife Sciences Publications Ltd
2018-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/37925 |
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| author | Lili Liao Zongzhi Z Liu Lauren Langbein Weijia Cai Eun-Ah Cho Jie Na Xiaohua Niu Wei Jiang Zhijiu Zhong Wesley L Cai Geetha Jagannathan Essel Dulaimi Joseph R Testa Robert G Uzzo Yuxin Wang George R Stark Jianxin Sun Stephen Peiper Yaomin Xu Qin Yan Haifeng Yang |
| author_facet | Lili Liao Zongzhi Z Liu Lauren Langbein Weijia Cai Eun-Ah Cho Jie Na Xiaohua Niu Wei Jiang Zhijiu Zhong Wesley L Cai Geetha Jagannathan Essel Dulaimi Joseph R Testa Robert G Uzzo Yuxin Wang George R Stark Jianxin Sun Stephen Peiper Yaomin Xu Qin Yan Haifeng Yang |
| author_sort | Lili Liao |
| collection | DOAJ |
| description | Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. |
| first_indexed | 2024-04-14T07:58:15Z |
| format | Article |
| id | doaj.art-469424e6a2dc4921b7e109a9d371cd8e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:58:15Z |
| publishDate | 2018-10-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj.art-469424e6a2dc4921b7e109a9d371cd8e2022-12-22T02:04:57ZengeLife Sciences Publications LtdeLife2050-084X2018-10-01710.7554/eLife.37925Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancerLili Liao0Zongzhi Z Liu1Lauren Langbein2https://orcid.org/0000-0002-3007-5287Weijia Cai3Eun-Ah Cho4Jie Na5Xiaohua Niu6Wei Jiang7Zhijiu Zhong8Wesley L Cai9Geetha Jagannathan10Essel Dulaimi11Joseph R Testa12Robert G Uzzo13Yuxin Wang14George R Stark15Jianxin Sun16Stephen Peiper17Yaomin Xu18https://orcid.org/0000-0002-3752-4006Qin Yan19https://orcid.org/0000-0003-4077-453XHaifeng Yang20https://orcid.org/0000-0002-0892-9055Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States; Department of Pathology, Yale University, Connecticut, United StatesDepartment of Pathology, Yale University, Connecticut, United StatesDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United StatesDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United StatesDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States; Fox Chase Cancer Center, Pennsylvania, United StatesDepartment of Health Sciences Research, Mayo Clinic, Minnesota, United StatesDepartment of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United StatesSidney Kimmel Cancer Center, Thomas Jefferson University, Pennsylvania, United StatesDepartment of Pathology, Yale University, Connecticut, United StatesDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United StatesFox Chase Cancer Center, Pennsylvania, United StatesFox Chase Cancer Center, Pennsylvania, United StatesFox Chase Cancer Center, Pennsylvania, United StatesDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Ohio, United StatesDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Ohio, United StatesDepartment of Medicine, Thomas Jefferson University, Pennsylvania, United StatesDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United StatesDepartment of Biostatistics, Vanderbilt University Medical Center, Tennessee, United States; Department of Biomedical Informatics, Vanderbilt University Medical Center, Tennessee, United StatesDepartment of Pathology, Yale University, Connecticut, United StatesDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United StatesWhereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC.https://elifesciences.org/articles/37925kidney cancerVHLPBRM1KDM5CBAP1ISGF3 |
| spellingShingle | Lili Liao Zongzhi Z Liu Lauren Langbein Weijia Cai Eun-Ah Cho Jie Na Xiaohua Niu Wei Jiang Zhijiu Zhong Wesley L Cai Geetha Jagannathan Essel Dulaimi Joseph R Testa Robert G Uzzo Yuxin Wang George R Stark Jianxin Sun Stephen Peiper Yaomin Xu Qin Yan Haifeng Yang Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer eLife kidney cancer VHL PBRM1 KDM5C BAP1 ISGF3 |
| title | Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer |
| title_full | Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer |
| title_fullStr | Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer |
| title_full_unstemmed | Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer |
| title_short | Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer |
| title_sort | multiple tumor suppressors regulate a hif dependent negative feedback loop via isgf3 in human clear cell renal cancer |
| topic | kidney cancer VHL PBRM1 KDM5C BAP1 ISGF3 |
| url | https://elifesciences.org/articles/37925 |
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