The Hexokinase "HKDC1" Interaction with the Mitochondria is Essential for Liver Cancer Progression

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Jul 28

PMID 35902556

Authors

Md Wasim Khan

Alexander R Terry

Medha Priyadarshini

Vladimir Ilievski

Zeenat Farooq

Grace Guzman

Jose Cordoba-Chacon

Issam Ben-Sahra

Barton Wicksteed

Brian T Layden

Affiliations

Soon will be listed here.

Abstract

Liver cancer (LC) is the fourth leading cause of death from cancer malignancies. Recently, a putative fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in LC compared to healthy liver tissue. Using a combination of in vitro and in vivo tools, we examined the role of HKDC1 in LC development and progression. Importantly, HKDC1 ablation stops LC development and progression via its action at the mitochondria by promoting metabolic reprogramming and a shift of glucose flux away from the TCA cycle. HKDC1 ablation leads to mitochondrial dysfunction resulting in less cellular energy, which cannot be compensated by enhanced glucose uptake. Moreover, we show that the interaction of HKDC1 with the mitochondria is essential for its role in LC progression, and without this interaction, mitochondrial dysfunction occurs. As HKDC1 is highly expressed in LC cells, but only to a minimal degree in hepatocytes under normal conditions, targeting HKDC1, specifically its interaction with the mitochondria, may represent a highly selective approach to target cancer cells in LC.

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