Reciprocal regulation of LOXL2 and HIF1\u03b1 drives the Warburg effect to support pancreatic cancer aggressiveness

Rongkun Li,Qing Li,Bo Ni,Lili Zhu,Shu-Heng Jiang,Zhigang Zhang,Lipeng Hu,Yanli Zhang,Xiaoxin Zhang,Xu Wang,Hengchao Li,Dejun Liu

doi:10.1038/s41419-021-04391-3

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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and lethal cancers and has been the seventh leading cause of cancer-related deaths worldwide [1, 2]
hypoxia-inducible factor 1α (HIF1α) dimerizes with HIF1β and binds to the hypoxia response elements (HREs) in the promoter regions of target genes involved in a plethora of pathophysiological processes
Cancer cells exhibit aberrant metabolism characterized by high glycolysis even with sufficient oxygen, a phenomenon known as aerobic glycolysis or the Warburg effect [10, 11]

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and lethal cancers and has been the seventh leading cause of cancer-related deaths worldwide [1, 2]. Hypoxic microenvironment is a common feature of solid tumors and is notable in PDAC due to poor blood flow caused by the desmoplastic reaction [4, 5]. HIF1 is comprised of HIF1α and HIF1β, wherein HIF1α serves as the major regulatory subunit responsible for its transcriptional function [7]. Both the stability and activity of HIF1α are oxygen-dependently regulated. HIF1α is hydroxylated by oxygen-dependent prolyl hydroxylases (PHDs), which enable the tumor suppressor von Hippel-Lindau (VHL) to bind to and mark HIF1α for rapid degradation through the ubiquitin-proteasome pathway. Prolyl hydroxylation of HIF1α is blocked, leading to HIF1α stabilization and nuclear translocation [6, 8]. HIF1α dimerizes with HIF1β and binds to the hypoxia response elements (HREs) in the promoter regions of target genes involved in a plethora of pathophysiological processes

Methods

Findings

Discussion

Conclusion