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

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.

A pan-cancer analysis of the role of hexokinase II (HK2) in human tumors

“…HK2 has been shown to interact with the mitochondria and contribute to liver cancer progression 25 . Recently, a fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in liver cancer compared to healthy liver tissue 26 . Studies revealed that inhibiting HK2-mediated glycolysis can enhance the anti-hepatocellular carcinoma activity of sorafenib 27 , 28 .…”

Mulberry-Derived 1-Deoxynojirimycin Prevents Type 2 Diabetes Mellitus Progression via Modulation of Retinol-Binding Protein 4 and Haptoglobin

“…Moreover, other proteins were predominantly present in the immune and inflammatory response pathways, such as proteins involving the activation of NF-κB, the acute phase reactant, and the TNF-α receptor ( Table 3 ). The proteins shown in the metabolic regulation pathway included phosphatidylinositol 3-kinase regulatory subunit beta (PIK3R2) and the insulin receptor, an important enzyme and receptor in the insulin signaling pathway [ 48 ], and putative hexokinase HKDC1, which is a hexokinase involved in glucose metabolism [ 49 ]. Although, we found some proteins that may play an important role in the insulin signaling pathway, the DNJ in the mulberry leaves could not maintain the prolonged action of those proteins after mulberry leaf supplementation.…”

Aiding Cancer’s “Sweet Tooth”: Role of Hexokinases in Metabolic Reprogramming

“…However, bacterial and lower vertebrate genes code for smaller proteins (about 50 kDa), while mammalian HKs 1-3 and HKDC1 are ≅ 100 kDa in size. HK isoforms possess high sequence similarities (Supplementary Fig 1) at the 'N' and 'C' terminal domains referred to as "Hemi domains" (Fig 1) [4][5][6][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. These hemi domains are thought to have evolved because of a gene duplication event from the bacterial HK enzyme [23,24].…”