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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Autores principales:	Xiulin Jiang, Yaomei He, Qiushuo Shen, Lincan Duan, Yixiao Yuan, Lin Tang, Yulin Shi, Baiyang Liu, Haoqing Zhai, Peng Shi, Cuiping Yang, Yongbin Chen
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	retinol saturase (RETSAT) hypoxia adaptation evolution Pin1 skin cutaneous melanoma (SKCM) Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5c2003fe2650440aa59338cf1d6c639c
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spelling	oai:doaj.org-article:5c2003fe2650440aa59338cf1d6c639c2021-11-04T06:54:37ZRETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth2296-634X10.3389/fcell.2021.744992https://doaj.org/article/5c2003fe2650440aa59338cf1d6c639c2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.744992/fullhttps://doaj.org/toc/2296-634XHypoxia 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.Xiulin JiangXiulin JiangYaomei HeYaomei HeQiushuo ShenLincan DuanYixiao YuanLin TangYulin ShiYulin ShiBaiyang LiuBaiyang LiuHaoqing ZhaiHaoqing ZhaiPeng ShiPeng ShiCuiping YangCuiping YangYongbin ChenYongbin ChenYongbin ChenFrontiers Media S.A.articleretinol saturase (RETSAT)hypoxia adaptationevolutionPin1skin cutaneous melanoma (SKCM)Biology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	retinol saturase (RETSAT) hypoxia adaptation evolution Pin1 skin cutaneous melanoma (SKCM) Biology (General) QH301-705.5
spellingShingle	retinol saturase (RETSAT) hypoxia adaptation evolution Pin1 skin cutaneous melanoma (SKCM) Biology (General) QH301-705.5 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
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.
format	article
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
title	RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth
title_short	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_sort	retsat mutation selected for hypoxia adaptation inhibits tumor growth
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/5c2003fe2650440aa59338cf1d6c639c
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RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth

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