RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth
Hypoxia occurs not only in natural environments including high altitude, underground burrows and deep sea, but also in human pathological conditions, such as hypoxic solid tumors. It has been well documented that hypoxia related signaling pathway is associated with a poor clinical outcome. Our group...
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| Format: | Article |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.744992/full |
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| author | Xiulin Jiang Xiulin Jiang Yaomei He Yaomei He Qiushuo Shen Lincan Duan Yixiao Yuan Lin Tang Yulin Shi Yulin Shi Baiyang Liu Baiyang Liu Haoqing Zhai Haoqing Zhai Peng Shi Peng Shi Cuiping Yang Cuiping Yang Yongbin Chen Yongbin Chen Yongbin Chen |
| author_facet | Xiulin Jiang Xiulin Jiang Yaomei He Yaomei He Qiushuo Shen Lincan Duan Yixiao Yuan Lin Tang Yulin Shi Yulin Shi Baiyang Liu Baiyang Liu Haoqing Zhai Haoqing Zhai Peng Shi Peng Shi Cuiping Yang Cuiping Yang Yongbin Chen Yongbin Chen Yongbin Chen |
| author_sort | Xiulin Jiang |
| collection | DOAJ |
| description | Hypoxia occurs not only in natural environments including high altitude, underground burrows and deep sea, but also in human pathological conditions, such as hypoxic solid tumors. It has been well documented that hypoxia related signaling pathway is associated with a poor clinical outcome. Our group has recently identified multiple novel genes critical for solid tumor growth comparing the genome-wide convergent/parallel sequence evolution of highland mammals. Among them, a single mutation on the retinol saturase gene (RETSAT) containing amino acid switch from glutamine (Q) to arginine (R) at the position 247 was identified. Here, we demonstrate that RETSAT is mostly downregulated in multiple types of human cancers, whose lower expression correlates with worse clinical outcome. We show that higher expression of RETSAT is positively associated with immune infiltration in different human cancers. Furthermore, we identify that the promoter region of RETSAT is highly methylated, which leads to its decreased expressions in tumor tissues comparing to normal tissues. Furthermore, we show that RETSAT knockdown promotes, while its overexpression inhibits, the cell proliferation ability of mouse embryonic fibroblasts (MEFs) and B16 in vitro. In addition, the mice carrying homozygous Q247R mutation (RETSATR/R) is more resistant to xenograft tumor formation, as well as DMBA/TPA induced cutaneous keratinocyte carcinoma formation, compared to littermate wild-type (RETSATQ/Q) mice. Mechanistic study uncovers that the oncogenic factor, the prolyl isomerase (PPIase) Pin1 and its related downstream signaling pathway, were both markedly repressed in the mutant mice compared to the wild-type mice. In summary, these results suggest that interdisciplinary study between evolution and tumor biology can facilitate identification of novel molecular events essential for hypoxic solid tumor growth in the future. |
| first_indexed | 2024-12-17T17:42:28Z |
| format | Article |
| id | doaj.art-5c2003fe2650440aa59338cf1d6c639c |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-17T17:42:28Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-5c2003fe2650440aa59338cf1d6c639c2022-12-21T21:39:09ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-11-01910.3389/fcell.2021.744992744992RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor GrowthXiulin Jiang0Xiulin Jiang1Yaomei He2Yaomei He3Qiushuo Shen4Lincan Duan5Yixiao Yuan6Lin Tang7Yulin Shi8Yulin Shi9Baiyang Liu10Baiyang Liu11Haoqing Zhai12Haoqing Zhai13Peng Shi14Peng Shi15Cuiping Yang16Cuiping Yang17Yongbin Chen18Yongbin Chen19Yongbin Chen20Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, ChinaKunming College of Life Science, University of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, ChinaKunming College of Life Science, University of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, ChinaThe Third Affiliated Hospital of Kunming Medical University, Kunming, ChinaThe Third Affiliated Hospital of Kunming Medical University, Kunming, ChinaThe Third Affiliated Hospital of Kunming Medical University, Kunming, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, ChinaKunming College of Life Science, University of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, ChinaKunming College of Life Science, University of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, ChinaKunming College of Life Science, University of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, ChinaCenter for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, ChinaKunming College of Life Science, University of Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, ChinaKunming College of Life Science, University of Chinese Academy of Sciences, Beijing, ChinaCenter for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, ChinaHypoxia occurs not only in natural environments including high altitude, underground burrows and deep sea, but also in human pathological conditions, such as hypoxic solid tumors. It has been well documented that hypoxia related signaling pathway is associated with a poor clinical outcome. Our group has recently identified multiple novel genes critical for solid tumor growth comparing the genome-wide convergent/parallel sequence evolution of highland mammals. Among them, a single mutation on the retinol saturase gene (RETSAT) containing amino acid switch from glutamine (Q) to arginine (R) at the position 247 was identified. Here, we demonstrate that RETSAT is mostly downregulated in multiple types of human cancers, whose lower expression correlates with worse clinical outcome. We show that higher expression of RETSAT is positively associated with immune infiltration in different human cancers. Furthermore, we identify that the promoter region of RETSAT is highly methylated, which leads to its decreased expressions in tumor tissues comparing to normal tissues. Furthermore, we show that RETSAT knockdown promotes, while its overexpression inhibits, the cell proliferation ability of mouse embryonic fibroblasts (MEFs) and B16 in vitro. In addition, the mice carrying homozygous Q247R mutation (RETSATR/R) is more resistant to xenograft tumor formation, as well as DMBA/TPA induced cutaneous keratinocyte carcinoma formation, compared to littermate wild-type (RETSATQ/Q) mice. Mechanistic study uncovers that the oncogenic factor, the prolyl isomerase (PPIase) Pin1 and its related downstream signaling pathway, were both markedly repressed in the mutant mice compared to the wild-type mice. In summary, these results suggest that interdisciplinary study between evolution and tumor biology can facilitate identification of novel molecular events essential for hypoxic solid tumor growth in the future.https://www.frontiersin.org/articles/10.3389/fcell.2021.744992/fullretinol saturase (RETSAT)hypoxia adaptationevolutionPin1skin cutaneous melanoma (SKCM) |
| spellingShingle | Xiulin Jiang Xiulin Jiang Yaomei He Yaomei He Qiushuo Shen Lincan Duan Yixiao Yuan Lin Tang Yulin Shi Yulin Shi Baiyang Liu Baiyang Liu Haoqing Zhai Haoqing Zhai Peng Shi Peng Shi Cuiping Yang Cuiping Yang Yongbin Chen Yongbin Chen Yongbin Chen RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth Frontiers in Cell and Developmental Biology retinol saturase (RETSAT) hypoxia adaptation evolution Pin1 skin cutaneous melanoma (SKCM) |
| title | RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth |
| title_full | RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth |
| title_fullStr | RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth |
| title_full_unstemmed | RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth |
| title_short | RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth |
| title_sort | retsat mutation selected for hypoxia adaptation inhibits tumor growth |
| topic | retinol saturase (RETSAT) hypoxia adaptation evolution Pin1 skin cutaneous melanoma (SKCM) |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.744992/full |
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