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

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.

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Cited by papers we hold 6

• Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2 · 2022
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• Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications · 2022
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• SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis · 2021
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• The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer · 2021
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• Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters · 2021
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• The role of ubiquitination and deubiquitination in cancer metabolism · 2020
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