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

Author

Listed:
  • Hong-Jen Lee

    (Stony Brook University
    Stony Brook University)

  • Chien-Feng Li

    (National Health Research Institutes
    Chi-Mei Foundational Medical Center)

  • Diane Ruan

    (Stony Brook University)

  • Jiabei He

    (Stony Brook University)

  • Emily D. Montal

    (Stony Brook University
    Stony Brook University)

  • Sonja Lorenz

    (University of Würzburg)

  • Geoffrey D. Girnun

    (Stony Brook University)

  • Chia-Hsin Chan

    (Stony Brook University
    Stony Brook University)

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.

Suggested Citation

  • Hong-Jen Lee & Chien-Feng Li & Diane Ruan & Jiabei He & Emily D. Montal & Sonja Lorenz & Geoffrey D. Girnun & Chia-Hsin Chan, 2019. "Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10374-y
    DOI: 10.1038/s41467-019-10374-y
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    Cited by:

    1. Mian Wang & Wanlu Li & Jin Hao & Arthur Gonzales & Zhibo Zhao & Regina Sanchez Flores & Xiao Kuang & Xuan Mu & Terry Ching & Guosheng Tang & Zeyu Luo & Carlos Ezio Garciamendez-Mijares & Jugal Kishore, 2022. "Molecularly cleavable bioinks facilitate high-performance digital light processing-based bioprinting of functional volumetric soft tissues," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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