HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition
Hypoxia is a universal pathological feature of solid tumors. Hypoxic tumor cells acquire metastatic and lethal phenotypes primarily through the activities of hypoxia-inducible factor 1 alpha (HIF1α). Therefore, HIF1α is considered as a promising therapeutic target. However, HIF inhibitors have not p...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.724059/full |
| _version_ | 1798035037077110784 |
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| author | Hao Geng Hyun-Kyung Ko Janet Pittsenbarger Christopher T. Harvey Changhui Xue Qiong Liu Sadie Wiens Sushant K. Kachhap Tomasz M. Beer David Z. Qian |
| author_facet | Hao Geng Hyun-Kyung Ko Janet Pittsenbarger Christopher T. Harvey Changhui Xue Qiong Liu Sadie Wiens Sushant K. Kachhap Tomasz M. Beer David Z. Qian |
| author_sort | Hao Geng |
| collection | DOAJ |
| description | Hypoxia is a universal pathological feature of solid tumors. Hypoxic tumor cells acquire metastatic and lethal phenotypes primarily through the activities of hypoxia-inducible factor 1 alpha (HIF1α). Therefore, HIF1α is considered as a promising therapeutic target. However, HIF inhibitors have not proven to be effective in clinical testing. The underlying mechanism is unclear. We report that oncogenic protein ID1 is upregulated in hypoxia by HIF1α shRNA or pharmacological inhibitors. In turn, ID1 supports tumor growth in hypoxia in vitro and in xenografts in vivo, conferring adaptive survival response and resistance. Mechanistically, ID1 proteins interfere HIF1-mediated gene transcription activation, thus ID1 protein degradation is accelerated by HIF1α-dependent mechanisms in hypoxia. Inhibitions of HIF1α rescues ID1, which compensates the loss of HIF1α by the upregulation of GLS2 and glutamine metabolism, thereby switching the metabolic dependency of HIF1α -inhibited cells from glucose to glutamine. |
| first_indexed | 2024-04-11T20:52:38Z |
| format | Article |
| id | doaj.art-3a9e4a94373f48bca52a168e994e4acf |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-11T20:52:38Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-3a9e4a94373f48bca52a168e994e4acf2022-12-22T04:03:47ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-11-01910.3389/fcell.2021.724059724059HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-InhibitionHao Geng0Hyun-Kyung Ko1Janet Pittsenbarger2Christopher T. Harvey3Changhui Xue4Qiong Liu5Sadie Wiens6Sushant K. Kachhap7Tomasz M. Beer8David Z. Qian9Prostate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesProstate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesProstate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesProstate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesProstate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesProstate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesProstate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United StatesProstate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesProstate Cancer Research Program, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United StatesHypoxia is a universal pathological feature of solid tumors. Hypoxic tumor cells acquire metastatic and lethal phenotypes primarily through the activities of hypoxia-inducible factor 1 alpha (HIF1α). Therefore, HIF1α is considered as a promising therapeutic target. However, HIF inhibitors have not proven to be effective in clinical testing. The underlying mechanism is unclear. We report that oncogenic protein ID1 is upregulated in hypoxia by HIF1α shRNA or pharmacological inhibitors. In turn, ID1 supports tumor growth in hypoxia in vitro and in xenografts in vivo, conferring adaptive survival response and resistance. Mechanistically, ID1 proteins interfere HIF1-mediated gene transcription activation, thus ID1 protein degradation is accelerated by HIF1α-dependent mechanisms in hypoxia. Inhibitions of HIF1α rescues ID1, which compensates the loss of HIF1α by the upregulation of GLS2 and glutamine metabolism, thereby switching the metabolic dependency of HIF1α -inhibited cells from glucose to glutamine.https://www.frontiersin.org/articles/10.3389/fcell.2021.724059/fullID1hypoxiaresistanceHIF1targeted-treatment |
| spellingShingle | Hao Geng Hyun-Kyung Ko Janet Pittsenbarger Christopher T. Harvey Changhui Xue Qiong Liu Sadie Wiens Sushant K. Kachhap Tomasz M. Beer David Z. Qian HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition Frontiers in Cell and Developmental Biology ID1 hypoxia resistance HIF1 targeted-treatment |
| title | HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition |
| title_full | HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition |
| title_fullStr | HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition |
| title_full_unstemmed | HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition |
| title_short | HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition |
| title_sort | hif1 and id1 interplay confers adaptive survival to hif1α inhibition |
| topic | ID1 hypoxia resistance HIF1 targeted-treatment |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.724059/full |
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