The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness

Thomas, Geethu Emily; Egan, Grace; García‐Prat, Laura; Botham, Aaron; Voisin, Véronique; Patel, Parasvi S.; Hoff, Fieke W.; Chin, Jordan; Nachmias, Boaz; Kaufmann, Kerstin B.; Khan, Dilshad H.; Hurren, Rose; Wang, Xiaoming; Gronda, Marcela; MacLean, Neil; O’Brien, Cristiana; Singh, Rashim; Jones, Courtney L.; Harding, Shane M.; Raught, Brian; Arruda, Andrea; Minden, Mark D.; Bader, Gary D.; Hakem, Razq; Kornblau, S.; Dick, John E.; Schimmer, Aaron D.

doi:10.1038/s41556-022-00925-9

Cited by 36 publications

(28 citation statements)

References 72 publications

(80 reference statements)

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“…Overexpressed HK2 has been found to promote, upon its nuclear localization, a stem cell phenotype in both acute myeloid leukemia (AML) and normal hematopoietic cells [ 113 ]. This was the consequence of HK2 becoming phosphorylated and having interacted with nuclear proteins known to regulate chromatin accessibility, leading to increased chromatin accessibility at DNA domains promoting stemness and DNA repair.…”

Section: Can Upregulated Glycolysis Play a Causative Role In Oncogene...mentioning

confidence: 99%

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On the Role of Glycolysis in Early Tumorigenesis—Permissive and Executioner Effects

Marcucci

Rumio

2023

Cells

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Reprogramming energy production from mitochondrial respiration to glycolysis is now considered a hallmark of cancer. When tumors grow beyond a certain size they give rise to changes in their microenvironment (e.g., hypoxia, mechanical stress) that are conducive to the upregulation of glycolysis. Over the years, however, it has become clear that glycolysis can also associate with the earliest steps of tumorigenesis. Thus, many of the oncoproteins most commonly involved in tumor initiation and progression upregulate glycolysis. Moreover, in recent years, considerable evidence has been reported suggesting that upregulated glycolysis itself, through its enzymes and/or metabolites, may play a causative role in tumorigenesis, either by acting itself as an oncogenic stimulus or by facilitating the appearance of oncogenic mutations. In fact, several changes induced by upregulated glycolysis have been shown to be involved in tumor initiation and early tumorigenesis: glycolysis-induced chromatin remodeling, inhibition of premature senescence and induction of proliferation, effects on DNA repair, O-linked N-acetylglucosamine modification of target proteins, antiapoptotic effects, induction of epithelial–mesenchymal transition or autophagy, and induction of angiogenesis. In this article we summarize the evidence that upregulated glycolysis is involved in tumor initiation and, in the following, we propose a mechanistic model aimed at explaining how upregulated glycolysis may play such a role.

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Section: Can Upregulated Glycolysis Play a Causative Role In Oncogene...mentioning

confidence: 99%

“…Histone O -GlcNacylation has also been shown to influence the chromatin structure and regulate gene expression [ 119 ]. Eventually, the effect of nuclear HK2 leading to an increase in open chromatin conformation has been discussed before [ 113 ].…”

Section: Mechanistic Aspects Of the Involvement Of Glycolysis In Earl...mentioning

confidence: 99%

On the Role of Glycolysis in Early Tumorigenesis—Permissive and Executioner Effects

Marcucci

Rumio

2023

Cells

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“…[SPIN1]), transcriptional regulators (e.g., interacts with Spt6 [IWS1]), and DNA damage responders (e.g., Sirtuin-1 [SIRT1]). The overall effect is to enhance chromatin accessibility to an array of HR-mediated repair proteins (Thomas et al, 2022). The next glycolytic enzyme with prominent influences on DSB repair is PFKFB3.…”

Section: Glycolysis Is the Metabolic Coordinator That Favors Homologo...mentioning

confidence: 99%

“…Beginning with hexokinase‐2 (HK2), this first enzyme of the glycolysis can be phosphorylated and subsequently translocated into the nucleus to regulate chromatin openness via interacting with other nuclear proteins, including chromatin organizers (e.g., Myc‐associated factor X [MAX] and spindling‐1 [SPIN1]), transcriptional regulators (e.g., interacts with Spt6 [IWS1]), and DNA damage responders (e.g., Sirtuin‐1 [SIRT1]). The overall effect is to enhance chromatin accessibility to an array of HR‐mediated repair proteins (Thomas et al, 2022). The next glycolytic enzyme with prominent influences on DSB repair is PFKFB3.…”

Section: The Central Carbon Metabolism Supports Ddr In Multiple Aspectsmentioning

confidence: 99%

Cross‐talk between DNA damage response and the central carbon metabolic network underlies selective vulnerability of Purkinje neurons in ataxia‐telangiectasia

Sun

Wong

Chow

2023

Journal of Neurochemistry

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Cerebellar ataxia is often the first and irreversible outcome in the disease of ataxia‐telangiectasia (A‐T), as a consequence of selective cerebellar Purkinje neuronal degeneration. A‐T is an autosomal recessive disorder resulting from the loss‐of‐function mutations of the ataxia‐telangiectasia–mutated ATM gene. Over years of research, it now becomes clear that functional ATM—a serine/threonine kinase protein product of the ATM gene—plays critical roles in regulating both cellular DNA damage response and central carbon metabolic network in multiple subcellular locations. The key question arises is how cerebellar Purkinje neurons become selectively vulnerable when all other cell types in the brain are suffering from the very same defects in ATM function. This review intended to comprehensively elaborate the unexpected linkages between these two seemingly independent cellular functions and the regulatory roles of ATM involved, their integrated impacts on both physical and functional properties, hence the introduction of selective vulnerability to Purkinje neurons in the disease will be addressed.image

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“…Accumulated evidence has indicated that glucose metabolism and the expression of HK2 may promote tumor chemoresistance. 12,13 By increasing the ubiquitination of pleckstrin homeodomain leucine-rich repeat protein phosphatase 2 and upregulating the expression of p-AKT, overexpression of wild-type tripartite motif 46 can promote the proliferation and glycolysis of lung adenocarcinoma (LUAD) cells and enhance their resistance to cisplatin. 14 Knockdown of HK2 expression can enhance the sensitivity of ovarian cancer to cisplatin.…”

Section: Introductionmentioning

confidence: 99%

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

Gao,

Huang,

Liu

et al. 2024

J of Cellular Biochemistry

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Despite surgical treatment combined with multidrug therapy having made some progress, chemotherapy resistance is the main cause of recurrence and death of gastric cancer (GC). Gastric cancer mesenchymal stem cells (GCMSCs) have been reported to be correlated with the limited efficacy of chemotherapy in GC, but the mechanism of GCMSCs regulating GC resistance needs to be further studied. The gene set enrichment analysis (GSEA) was performed to explore the glycolysis‐related pathways heterogeneity across different cell subpopulations. Glucose uptake and lactate production assays were used to evaluate the importance of B7H3 expression in GCMSCs‐treated GC cells. The therapeutic efficacy of oxaliplatin (OXA) and paclitaxel (PTX) was determined using CCK‐8 and colony formation assays. Signaling pathways altered by GCMSCs‐CM were revealed by immunoblotting. The expression of TNF‐α in GCMSCs and bone marrow mesenchymal stem cells (BMMSCs) was detected by western blot analysis and qPCR. Our results showed that the OXA and PTX resistance of GC cells were significantly enhanced in the GCMSCs‐CM treated GC cells. Acquired OXA and PTX resistance was characterized by increased cell viability for OXA and PTX, the formation of cell colonies, and decreased levels of cell apoptosis, which were accompanied by reduced levels of cleaved caspase‐3 and Bax expression, and increased levels of Bcl‐2, HK2, MDR1, and B7H3 expression. Blocking TNF‐α in GCMSCs‐CM, B7H3 knockdown or the use of 2‐DG, a key enzyme inhibitor of glycolysis in GC cells suppressed the OXA and PTX resistance of GC cells that had been treated with GCMSCs‐CM. This study shows that GCMSCs‐CM derived TNF‐α could upregulate the expression of B7H3 of GC cells to promote tumor chemoresistance. Our results provide a new basis for the treatment of GC.

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The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness

Cited by 36 publications

References 72 publications

On the Role of Glycolysis in Early Tumorigenesis—Permissive and Executioner Effects

On the Role of Glycolysis in Early Tumorigenesis—Permissive and Executioner Effects

Cross‐talk between DNA damage response and the central carbon metabolic network underlies selective vulnerability of Purkinje neurons in ataxia‐telangiectasia

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells

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