Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer

Author:

Zhang Misty Shuo,Cui Jane Di,Lee DerekORCID,Yuen Vincent Wai-Hin,Chiu David Kung-Chun,Goh Chi Ching,Cheu Jacinth Wing-Sum,Tse Aki Pui-Wah,Bao Macus Hao-Ran,Wong Bowie Po Yee,Chen Carrie Yiling,Wong Chun-MingORCID,Ng Irene Oi-LinORCID,Wong Carmen Chak-LuiORCID

Abstract

AbstractHepatocellular carcinoma (HCC) invariably exhibits inadequate O2 (hypoxia) and nutrient supply. Hypoxia-inducible factor (HIF) mediates cascades of molecular events that enable cancer cells to adapt and propagate. Macropinocytosis is an endocytic process initiated by membrane ruffling, causing the engulfment of extracellular fluids (proteins), protein digestion and subsequent incorporation into the biomass. We show that macropinocytosis occurs universally in HCC under hypoxia. HIF-1 activates the transcription of a membrane ruffling protein, EH domain-containing protein 2 (EHD2), to initiate macropinocytosis. Knockout of HIF-1 or EHD2 represses hypoxia-induced macropinocytosis and prevents hypoxic HCC cells from scavenging protein that support cell growth. Germline or somatic deletion of Ehd2 suppresses macropinocytosis and HCC development in mice. Intriguingly, EHD2 is overexpressed in HCC. Consistently, HIF-1 or macropinocytosis inhibitor suppresses macropinocytosis and HCC development. Thus, we show that hypoxia induces macropinocytosis through the HIF/EHD2 pathway in HCC cells, harnessing extracellular protein as a nutrient to survive.

Funder

Research Grants Council, University Grants Committee

National Natural Science Foundation of China

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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