Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion

Hong-Jen Lee,Jiabei He,Chia-Hsin Chan,Diane Ruan,Chien-Feng Li,Sonja Lorenz,Geoffrey D Girnun,Emily D Montal

doi:10.1038/s41467-019-10374-y

Abstract

Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.

Highlights

Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies
We showed that HectH9 expression in prostate cancer cells is upregulated upon hypoxia (Supplementary Fig. 1a)
To study HectH9’s potential role in glucose metabolism, we examined if HectH9 is involved in the glucose dependency of prostate cancer cells

Summary

Introduction

Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis. Most tumors increase their glucose metabolism to meet increased energy, biosynthesis and redox needs. Does accelerated glucose metabolism represent a hallmark of cancer cells, it contributes directly to biological processes regulating the growth, dissemination and treatment resistance of tumors[1,2,3]. Recent studies have established the cancer-promoting function of mitochondrial oxidative phosphorylation (OXPHOS) by regulating cell growth and redox homeostasis[6]. We show that HectH9 promotes HK2’s K63linked ubiquitination: this post-translational modification regulates HK2’s localization to mitochondria and the subsequent functions in glycolysis induction and apoptosis prevention. Our results illustrate that blocking the HectH9/HK2 pathway inhibits ROS-mediated CSC expansion and tumor development, providing a new roadmap to combat drug-resistant tumors

Methods

Results

Conclusion