HIF2 Regulates Intestinal Wnt5a Expression

Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through t...

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Autores principales:	Carolina J. García García, Ariana C. Acevedo Diaz, Neeraj Kumari, Suman Govindaraju, Marimar de la Cruz Bonilla, F. Anthony San Lucas, Nicholas D. Nguyen, Iancarlos Jiménez Sacarello, Helen Piwnica-Worms, Anirban Maitra, Cullen M. Taniguchi
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	radiotherapy intestinal stem cells GI radiotoxicity hypoxia HIF2 Wnt5a Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/05fcc8c992f74d3c958d1640320a0cbb
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spelling	oai:doaj.org-article:05fcc8c992f74d3c958d1640320a0cbb2021-12-01T01:54:06ZHIF2 Regulates Intestinal Wnt5a Expression2234-943X10.3389/fonc.2021.769385https://doaj.org/article/05fcc8c992f74d3c958d1640320a0cbb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.769385/fullhttps://doaj.org/toc/2234-943XRadiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.Carolina J. García GarcíaCarolina J. García GarcíaCarolina J. García GarcíaCarolina J. García GarcíaAriana C. Acevedo DiazNeeraj KumariNeeraj KumariSuman GovindarajuMarimar de la Cruz BonillaMarimar de la Cruz BonillaMarimar de la Cruz BonillaF. Anthony San LucasNicholas D. NguyenNicholas D. NguyenIancarlos Jiménez SacarelloHelen Piwnica-WormsAnirban MaitraCullen M. TaniguchiCullen M. TaniguchiFrontiers Media S.A.articleradiotherapyintestinal stem cellsGI radiotoxicityhypoxiaHIF2Wnt5aNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	radiotherapy intestinal stem cells GI radiotoxicity hypoxia HIF2 Wnt5a Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	radiotherapy intestinal stem cells GI radiotoxicity hypoxia HIF2 Wnt5a Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Carolina J. García García Carolina J. García García Carolina J. García García Carolina J. García García Ariana C. Acevedo Diaz Neeraj Kumari Neeraj Kumari Suman Govindaraju Marimar de la Cruz Bonilla Marimar de la Cruz Bonilla Marimar de la Cruz Bonilla F. Anthony San Lucas Nicholas D. Nguyen Nicholas D. Nguyen Iancarlos Jiménez Sacarello Helen Piwnica-Worms Anirban Maitra Cullen M. Taniguchi Cullen M. Taniguchi HIF2 Regulates Intestinal Wnt5a Expression
description	Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.
format	article
author	Carolina J. García García Carolina J. García García Carolina J. García García Carolina J. García García Ariana C. Acevedo Diaz Neeraj Kumari Neeraj Kumari Suman Govindaraju Marimar de la Cruz Bonilla Marimar de la Cruz Bonilla Marimar de la Cruz Bonilla F. Anthony San Lucas Nicholas D. Nguyen Nicholas D. Nguyen Iancarlos Jiménez Sacarello Helen Piwnica-Worms Anirban Maitra Cullen M. Taniguchi Cullen M. Taniguchi
author_facet	Carolina J. García García Carolina J. García García Carolina J. García García Carolina J. García García Ariana C. Acevedo Diaz Neeraj Kumari Neeraj Kumari Suman Govindaraju Marimar de la Cruz Bonilla Marimar de la Cruz Bonilla Marimar de la Cruz Bonilla F. Anthony San Lucas Nicholas D. Nguyen Nicholas D. Nguyen Iancarlos Jiménez Sacarello Helen Piwnica-Worms Anirban Maitra Cullen M. Taniguchi Cullen M. Taniguchi
author_sort	Carolina J. García García
title	HIF2 Regulates Intestinal Wnt5a Expression
title_short	HIF2 Regulates Intestinal Wnt5a Expression
title_full	HIF2 Regulates Intestinal Wnt5a Expression
title_fullStr	HIF2 Regulates Intestinal Wnt5a Expression
title_full_unstemmed	HIF2 Regulates Intestinal Wnt5a Expression
title_sort	hif2 regulates intestinal wnt5a expression
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/05fcc8c992f74d3c958d1640320a0cbb
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HIF2 Regulates Intestinal Wnt5a Expression

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