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

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. Mitochondrial interaction of HKDC1 is essential for its pro-proliferative role in LC. When HKDC1 is ablated in liver cancer cells, mitochondrial dysfunction occurs which results in decrease ATP in the cells. The cancer cells react to decreased cellular energy by increasing glucose uptake. Also due to mitochondrial dysfunction there is enhanced ER stress and ER-mitochondrial interaction, leading to more calcium flux into the mitochondria. This multi-pronged effects of HKDC1 ablation leads to decreased cellular proliferation in LC.