The Role of Protein SUMOylation in Human Hepatocellular Carcinoma: A Potential Target of New Drug Discovery and Development

Yuan, Hongchao; Lu, Yuanjun; Zhang, Cheng; Wang, Ning; Feng, Yibin

doi:10.3390/cancers13225700

Cited by 13 publications

(11 citation statements)

References 102 publications

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“…DNA damage response (DDR) is a complex signal transduction pathway that is able to repair various endogenous and exogenous DNA lesions that accumulate in cells [ 64 , 65 ]. Phosphorylation, ubiquitination, and sumoylation are part of the critical post-translational alterations that occur on DNA damage response genes, the latter being necessary for proper repair [ 66 ]. Although DNA repair protein impairment usually leads to apoptosis, cells may also experience genomic degradation according to the degree of damage [ 65 ].…”

Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Khaled

Kopsida

Lennernäs

et al. 2022

Cells

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Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.

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Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Khaled

Kopsida

Lennernäs

et al. 2022

Cells

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“…However, the mechanism underlying the regulation of miR-122 in liver cancer is still not fully revealed. Considering that SUMOylation has been shown to play a crucial role in various processes of liver cancer (21,26,27), we speculate whether the regulatory role of miR-122 in liver cancer is partly related to SUMOylation. Based on the ENCORI database, 1,278 potential target genes of miR-122 were predicted.…”

Section: Senp1 Is Predicted and Confirmed As A Direct Target Of Mir-122mentioning

confidence: 96%

miR‑122/SENP1 axis confers stemness and chemoresistance to liver cancer through Wnt/β‑catenin signaling

Dai

Hao

Chen³

et al. 2023

Oncol Lett

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The property of inherent stemness of tumor cells coupled with the development of chemoresistance results in a poor prognosis for patients with liver cancer. Therefore, the present study focused on microRNA (miR)-122, a potential tumor suppressor, the expression of which has been previously shown to be significantly decreased and negatively associated with cancer cell stemness in liver cancer. The present study aimed to identify the molecular targets of miR-122 whilst uncovering the mechanism underlying chemoresistance and stemness of HepG2 cells in liver cancer. Bioinformatics online tools, such as ENCORI, coupled with dual-luciferase reporter assays in HepG2 cells, were used to identify and validate small ubiquitin-like modifier (SUMO) specific peptidase 1 (SENP1) as a potential target of miR-122 in liver cancer. The liver cancer stem cell population was determined using sphere formation assays and flow cytometry, whilst stem cell markers (Oct3/4, Nanog, B lymphoma Mo-MLV insertion region 1 homolog and Notch1) were detected by reverse transcription-quantitative PCR. Chemoresistance, cell proliferation and migratory ability of HepG2 cells were monitored using Cell Counting Kit-8, colony formation and Transwell assays, respectively. The overexpression of miR-122 by mimic transfection led to a significant decrease in the number spheres, downregulation of stem cell marker expression, the number of CD24 + cells, drug-resistance protein levels (P-glycoprotein and multidrug resistance protein), impaired chemoresistance, proliferation and migration of HepG2 cells. The transfection of SENP1 overexpression vector resulted in contrasting functions to miR-122 mimics, by partially reversing the effects induced by miR-122 mimic transfection in HepG2 cells. Wnt/β-catenin signaling has been proven to be involved in cancer stemness and malignant behavior. Western blotting analysis in HepG2 cells showed that the expression levels of both Wnt1 and β-catenin were significantly reduced after overexpressing miR-122, but increased after overexpressing SENP1. Co-transfection with the SENP1 overexpression vector reversed the suppression induced by the miR-122 mimics on Wnt1 and β-catenin expression. Co-immunoprecipitation, SUMOylation and half-life assays showed SENP1 interacted with β-catenin and decreased the SUMOylation of β-catenin, thereby enhancing its stability. Finally, tumor xenograft analyses revealed that HepG2 cells transfected with Agomir-122 exerted significantly lower tumor initiation frequency and growth rate, and a superior response to DOX in vivo, compared with those transfected with Agomir NC. Taken together, data from the present study miR-122/SENP1 axis can regulate β-catenin stability through de-SUMOylation, thereby promoting stemness and chemoresistance in liver cancer.

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“…SUMO2 and SUMO3 have a specific N-terminus that allows the formation of multimers. SUMO4 and SUMO5 are the least well known SUMO paralogues, although their expression is restricted to specific tissues: SUMO4 is mainly expressed in kidney, spleen and lymph nodes, while SUMO5 is expressed only in few tissues, especially blood and testis ( Bouchard et al, 2021 ; Yuan et al, 2021 ).…”

Section: Post-translational Modificationsmentioning

confidence: 99%

SUMOylation and NEDDylation in Primary and Metastatic Cancers to Bone

Lombardi

Maroni

2022

Front. Cell Dev. Biol.

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Post-translational modifications comprise series of enzymatically-driven chemical modifications, virtually involving the entire cell proteome, that affect the fate of a target protein and, in turn, cell activity. Different classes of modifications can be established ranging from phosphorylation, glycosylation, ubiquitination, acetylation, methylation, lipidation and their inverse reactions. Among these, SUMOylation and NEDDylation are ubiquitin-like multi-enzymatic processes that determine the bound of SUMOs and NEDD8 labels, respectively, on defined amino acidic residues of a specific protein and regulate protein function. As fate-determinants of several effectors and mediators, SUMOylation and NEDDylation play relevant roles in many aspects of tumor cell biology. Bone represents a preferential site of metastasis for solid tumors (e.g., breast and prostate cancers) and the primary site of primitive tumors (e.g., osteosarcoma, chondrosarcoma). Deregulation of SUMOylation and NEDDylation affects different aspects of neoplastic transformation and evolution such as epithelial-mesenchymal transition, adaptation to hypoxia, expression and action of tumor suppressors and oncogenic mediators, and drug resistance. Thereby, they represent potential therapeutic targets. This narrative review aims at describing the involvement and regulation of SUMOylation and NEDDylation in tumor biology, with a specific focus on primary and secondary bone tumors, and to summarize and highlight their potentiality in diagnostics and therapeutic strategies.

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The Role of Protein SUMOylation in Human Hepatocellular Carcinoma: A Potential Target of New Drug Discovery and Development

Cited by 13 publications

References 102 publications

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

miR‑122/SENP1 axis confers stemness and chemoresistance to liver cancer through Wnt/β‑catenin signaling

SUMOylation and NEDDylation in Primary and Metastatic Cancers to Bone

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