Impact of posttranslational modifications in pancreatic carcinogenesis and treatments

Chen, Nianhong; Zheng, Qingfei; Wan, Guoqing; Guo, Feng; Zeng, Xiaobin; Shi, Ping

doi:10.1007/s10555-021-09980-4

Cited by 7 publications

(6 citation statements)

References 194 publications

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“…The function of desmosomal proteins in cancer is further modulated by phosphorylation [20,44–46]. Both protein levels and post‐translational modifications are major determinants of cell phenotypes, are necessary to maintain cell viability and function, and are implicated in several disease states including cancer [47,48]. Interestingly, we found that DSG2 may interact with multiple kinases, including PRKD2, PKM, PFKP, PRKCI, and EGFR.…”

Section: Discussionmentioning

confidence: 99%

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Liu,

Xu,

Zheng

et al. 2024

The Journal of Pathology

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Desmoglein‐2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell–cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine‐protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2‐T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2‐mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Liu,

Xu,

Zheng

et al. 2024

The Journal of Pathology

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“…Dysregulation of SUMOylation has been implicated in many pathological diseases such as cancer [ 23 , 24 ]. Whereas SIRT3 SUMOylation deficiency overcomes high-fat diet (HFD) induced obesity in mice under fasting conditions has been documented by our previous study [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

Zhang

Shen

Wei

et al. 2022

IJMS

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Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML.

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“…Therefore, their dysregulation usually leads to disease. Ubiquitination is one of the PTMs which can be involved in various pathological processes including pancreatic pathogenesis [ 7 ]. Deubiquitination is the reverse process of ubiquitination by the function of deubiquitinating enzymes (DUBs).…”

Section: Introductionmentioning

confidence: 99%

USPs in Pancreatic Ductal Adenocarcinoma: A Comprehensive Bioinformatic Analysis of Expression, Prognostic Significance, and Immune Infiltration

Wang

Zhou

Kong

et al. 2022

BioMed Research International

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Pancreatic ductal adenocarcinoma (PDAC), as an intractable malignancy, still causes an extremely high mortality worldwide. The ubiquitin-specific protease (USP) family constitutes the major part of deubiquitinating enzymes (DUBs) which has been reported to be involved in initiation and progression of various malignancies via the function of deubiquitination. However, the biological function and clinical values of USPs in PDAC have not been comprehensively elucidated. In this study, Gene Expression Profiling Interactive Analysis (GEPIA), Gene Expression Omnibus (GEO) datasets, UALCAN database, and the Human Protein Atlas (HPA) online tool were used to analyze the expression level and the relationship between USP expression and clinicopathological features in PDAC. Survival module of HPA and Kaplan-Meier plotter (KMP) databases was recruited to explore the prognostic value of USPs. Tumor Immune Estimation Resource (TIMER) online tool and KMP databases were utilized to elucidate tumor immune infiltration and immune-related survival of USPs. CBioPortal online tool was used to identify the gene mutation level of USPs in PDAC. Both cBioPortal and LinkedOmics were used to confirm the potential biological functions of USPs in PDAC. Our study showed that USP10, USP14, USP18, USP32, USP33, and USP39 (termed as six-USPs) expressions were significantly elevated in tumor tissues. The high expression of the four USPs (USP10, USP14, USP18, and USP39) indicated a poor prognosis. A significant relationship was indicated between the expression of six-USPs and clinicopathological features. Also, the expression of six-USPs was related to promoter methylation level. Moreover, more than 40% genetic alterations and mutations were discovered in six-USPs. Furthermore, the six-USP expression was correlated with immune infiltration and immune-related prognosis. The functional analysis found that the six-USPs were involved in various biological processes and signaling pathways, such as nucleocytoplasmic transport, choline metabolism in cancer, cell cycle, ErbB signaling pathway, RIG-I-like receptor signaling pathway, TGF-β signaling pathway, and TNF signaling pathway. In conclusion, the results showed that six-USPs are potential prognostic biomarkers and can be recruited as possible therapeutic targets of PDAC.

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Impact of posttranslational modifications in pancreatic carcinogenesis and treatments

Cited by 7 publications

References 194 publications

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

USPs in Pancreatic Ductal Adenocarcinoma: A Comprehensive Bioinformatic Analysis of Expression, Prognostic Significance, and Immune Infiltration

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