The hexokinase “HKDC1” interaction with the mitochondria is essential for liver cancer progression

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

doi:10.1038/s41419-022-04999-z

The hexokinase “HKDC1” interaction with the mitochondria is essential for liver cancer progression

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^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English (US)
Article number	660
Journal	Cell Death and Disease
Volume	13
Issue number	7
DOIs	https://doi.org/10.1038/s41419-022-04999-z
State	Published - Jul 2022

Funding

Liver cancer cell lines (SNU-387, 475) were kindly donated by Ron C. Gaba (Radiology & Pathology, UIC). Liver cancer cell lines (Hep3B2 and Huh7 were kindly donated by Dr. Nissim Hay (Department of Biochemistry and Molecular Genetics, UIC). Histology was done at the Research Histology Core (University of Illinois at Chicago) and imaging was done by Research Tissue Imaging Core (University of Illinois at Chicago). Transmission Electron Microscopy was done by Electron Microscope Core (University of Illinois at Chicago). Flow cytometry was done at Flow Cytometry Core (University of Illinois at Chicago). BTL is supported by a VA Merit Review Award (I01BX00382), NIH grants (R01 DK104927, R01 DK111848, U01 DK127378, and P30 DK020595). MWK is supported by DOD Career Development Grant (W81XWH2010650).

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41419-022-04999-z

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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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AU - Guzman, Grace

AU - Cordoba-Chacon, Jose

AU - Ben-Sahra, Issam

AU - Wicksteed, Barton

AU - Layden, Brian T.

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AB - 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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The hexokinase “HKDC1” interaction with the mitochondria is essential for liver cancer progression

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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