Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness

Abstract Hypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. In this study, we identify...

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Autores principales:	Rongkun Li, Hengchao Li, Lili Zhu, Xiaoxin Zhang, Dejun Liu, Qing Li, Bo Ni, Lipeng Hu, Zhigang Zhang, Yanli Zhang, Xu Wang, Shu-Heng Jiang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/a9866d1660f44f8aa236aeb1f6f49da1
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spelling	oai:doaj.org-article:a9866d1660f44f8aa236aeb1f6f49da12021-11-28T12:04:37ZReciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness10.1038/s41419-021-04391-32041-4889https://doaj.org/article/a9866d1660f44f8aa236aeb1f6f49da12021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04391-3https://doaj.org/toc/2041-4889Abstract Hypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. In this study, we identify that lysyl oxidase-like 2 (LOXL2) is a hypoxia-responsive gene and is essential for the Warburg effect in PDAC. LOXL2 stabilizes hypoxia-inducible factor 1α (HIF1α) from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, thereby facilitating the transcription of multiple glycolytic genes. Therefore, a positive feedback loop exists between LOXL2 and HIF1α that facilitates glycolytic metabolism under hypoxia. Moreover, LOXL2 couples the Warburg effect to tumor growth and metastasis in PDAC. Hijacking glycolysis largely compromises LOXL2-induced oncogenic activities. Collectively, our results identify a hitherto unknown hypoxia-LOXL2-HIF1α axis in regulating the Warburg effect and provide an intriguing drug target for PDAC therapy.Rongkun LiHengchao LiLili ZhuXiaoxin ZhangDejun LiuQing LiBo NiLipeng HuZhigang ZhangYanli ZhangXu WangShu-Heng JiangNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 12, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Rongkun Li Hengchao Li Lili Zhu Xiaoxin Zhang Dejun Liu Qing Li Bo Ni Lipeng Hu Zhigang Zhang Yanli Zhang Xu Wang Shu-Heng Jiang Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness
description	Abstract Hypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. In this study, we identify that lysyl oxidase-like 2 (LOXL2) is a hypoxia-responsive gene and is essential for the Warburg effect in PDAC. LOXL2 stabilizes hypoxia-inducible factor 1α (HIF1α) from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, thereby facilitating the transcription of multiple glycolytic genes. Therefore, a positive feedback loop exists between LOXL2 and HIF1α that facilitates glycolytic metabolism under hypoxia. Moreover, LOXL2 couples the Warburg effect to tumor growth and metastasis in PDAC. Hijacking glycolysis largely compromises LOXL2-induced oncogenic activities. Collectively, our results identify a hitherto unknown hypoxia-LOXL2-HIF1α axis in regulating the Warburg effect and provide an intriguing drug target for PDAC therapy.
format	article
author	Rongkun Li Hengchao Li Lili Zhu Xiaoxin Zhang Dejun Liu Qing Li Bo Ni Lipeng Hu Zhigang Zhang Yanli Zhang Xu Wang Shu-Heng Jiang
author_facet	Rongkun Li Hengchao Li Lili Zhu Xiaoxin Zhang Dejun Liu Qing Li Bo Ni Lipeng Hu Zhigang Zhang Yanli Zhang Xu Wang Shu-Heng Jiang
author_sort	Rongkun Li
title	Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness
title_short	Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness
title_full	Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness
title_fullStr	Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness
title_full_unstemmed	Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness
title_sort	reciprocal regulation of loxl2 and hif1α drives the warburg effect to support pancreatic cancer aggressiveness
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/a9866d1660f44f8aa236aeb1f6f49da1
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Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness

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