SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis

Shangguan, Xun; He, Jianli; Ma, Zehua; Zhang, Weiwei; Ji, Yiyi; Shen, Kai; Yue, Zhiying; Li, Wenyu; Zheng, Xiaoyang; Zheng, Quan; Cao, Ying; Pan, Jiahua; Dong, Baijun; Cheng, Jinke; Wang, Qi; Xue, Wei

doi:10.1038/s41467-021-22163-7

Cited by 85 publications

(72 citation statements)

References 42 publications

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“…Both Thr-473 and Lys-63 are absent in the other HK isozymes, suggesting that HK2 binding to mitochondria underpins unique and distinct biochemical functions. In addition, it was recently demonstrated that HK2 can be SUMOylated at Lys-315 and Lys-492 residues and that de-SUMOylated HK2 preferably binds to mitochondria [ 81 ].…”

Section: Hk2 On Mitochondria Of Neoplastic Cells: Maintaining the Bad Guy In Perfect Shapementioning

confidence: 99%

Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

Ciscato

Ferrone

Masgras

et al. 2021

IJMS

124

103

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Hexokinases are a family of ubiquitous exose-phosphorylating enzymes that prime glucose for intracellular utilization. Hexokinase 2 (HK2) is the most active isozyme of the family, mainly expressed in insulin-sensitive tissues. HK2 induction in most neoplastic cells contributes to their metabolic rewiring towards aerobic glycolysis, and its genetic ablation inhibits malignant growth in mouse models. HK2 can dock to mitochondria, where it performs additional functions in autophagy regulation and cell death inhibition that are independent of its enzymatic activity. The recent definition of HK2 localization to contact points between mitochondria and endoplasmic reticulum called Mitochondria Associated Membranes (MAMs) has unveiled a novel HK2 role in regulating intracellular Ca2+ fluxes. Here, we propose that HK2 localization in MAMs of tumor cells is key in sustaining neoplastic progression, as it acts as an intersection node between metabolic and survival pathways. Disrupting these functions by targeting HK2 subcellular localization can constitute a promising anti-tumor strategy.

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Section: Hk2 On Mitochondria Of Neoplastic Cells: Maintaining the Bad Guy In Perfect Shapementioning

confidence: 99%

Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

Ciscato

Ferrone

Masgras

et al. 2021

IJMS

124

103

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“…PTEN is considered to serve as a barrier for SENP1-induced PCa tumorigenesis, and the inhibition of SENP1 may be a therapeutic option for treatment of aggressive PTEN-deficient PCa. SUMOylation controls the subcellular localization of hexokinase 2 (HK2), which is a regulator of glycolysis and has oncogenic potential when it binds to mitochondria [239]. SENP1-induced deSUMOylation stimulates HK2 binding with mitochondria to promote metabolic reprogramming, supporting proliferation of PCa cells and protecting them from chemotherapy-mediated apoptosis.…”

Section: Prostate Cancermentioning

confidence: 99%

“…Dysregulation of SUMO pathway can also promote resistance towards several anti-cancer drugs, such as the proteasome inhibitor bortezomib in MM, anti-estrogens in breast cancer and different chemotherapeutics. Docetaxel resistance in PCa can be triggered via overexpression of the SENP1-HK2 axis or overexpression of PIAS1, further emphasizing heterogeneity of SUMO-dysregulation in cancer [239,303]. Hypoxia-induced SUMOylation of self-renewal and pluripotency regulator OCT4 decreases its level in embryonal carcinoma cells and promotes cisplatin and bleomycin resistance that can be counteracted with the induction of SENP1 overexpression [304].…”

Section: Potential Rational Combinationsmentioning

confidence: 99%

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Kukkula

Ojala

Mendez

et al. 2021

Cancers

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SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

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“…Increasing evidences have proven that the excessive activation of glycolysis mediates cell proliferation, resistance to chemotherapy, the immune response, and distant metastasis ( 15 , 37 – 39 ), so targeting aerobic glycolysis has become a promising treatment strategy ( 40 ). In the present study, the molecular functions of five glycolytic genes were investigated in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…This unique metabolic signature termed Warburg effect has been demonstrated to exist in various solid tumors, including PCa (12)(13)(14). Recently, an increasing number of studies have reported that abnormal expression of glycolysisrelated molecules have crucial roles in regulating chemotherapy resistance (15), immune response (16,17), neuroendocrine differentiation (18), and growth and metastasis of PCa (19,20), ultimately affecting its prognosis. Additionally, some researchers have successfully constructed prediction models derived from glycolysis-associated genes in liver cancer and colon cancer (4,21).…”

Section: Introductionmentioning

confidence: 99%

A Novel Risk Factor Model Based on Glycolysis-Associated Genes for Predicting the Prognosis of Patients With Prostate Cancer

et al. 2021

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BackgroundProstate cancer (PCa) is one of the most prevalent cancers among males, and its mortality rate is increasing due to biochemical recurrence (BCR). Glycolysis has been proven to play an important regulatory role in tumorigenesis. Although several key regulators or predictors involved in PCa progression have been found, the relationship between glycolysis and PCa is unclear; we aimed to develop a novel glycolysis-associated multifactor prediction model for better predicting the prognosis of PCa.MethodsDifferential mRNA expression profiles derived from the Cancer Genome Atlas (TCGA) PCa cohort were generated through the “edgeR” package. Glycolysis-related genes were obtained from the GSEA database. Univariate Cox and LASSO regression analyses were used to identify genes significantly associated with disease-free survival. ROC curves were applied to evaluate the predictive value of the model. An external dataset derived from Gene Expression Omnibus (GEO) was used to verify the predictive ability. Glucose consumption and lactic production assays were used to assess changes in metabolic capacity, and Transwell assays were used to assess the invasion and migration of PC3 cells.ResultsFive glycolysis-related genes were applied to construct a risk score prediction model. Patients with PCa derived from TCGA and GEO (GSE70770) were divided into high-risk and low-risk groups according to the median. In the TCGA cohort, the high-risk group had a poorer prognosis than the low-risk group, and the results were further verified in the GSE70770 cohort. In vitro experiments demonstrated that knocking down HMMR, KIF20A, PGM2L1, and ANKZF1 separately led to less glucose consumption, less lactic production, and inhibition of cell migration and invasion, and the results were the opposite with GPR87 knockdown.ConclusionThe risk score based on five glycolysis-related genes may serve as an accurate prognostic marker for PCa patients with BCR.

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SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis

Cited by 85 publications

References 42 publications

Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

A Novel Risk Factor Model Based on Glycolysis-Associated Genes for Predicting the Prognosis of Patients With Prostate Cancer

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