Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

Chen, Yifan; Shao, Xuejing; Cao, Ji; Zhu, Hong; Yang, Bo; He, Qiaojun

doi:10.1016/j.apsb.2020.09.007

Cited by 43 publications

(30 citation statements)

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“…This metabolic reprogramming gives HCC cells a growth advantage by providing energy for cancer cell growth and other metabolic intermediates for various processes ( 14 ). As a multi-step process, its progress is tightly regulated by three key rate-limiting enzymes (Hexokinase, PFK and PKM2) ( 15 ). In this study, we established that the highly expressed DNAAF5 proteins in HCC promote the malignant progression of tumor cells by increasing PFKL protein levels.…”

Section: Discussionmentioning

confidence: 99%

“…Theoretically, this implies that even under aerobic conditions, tumor cells preferentially perform glycolysis rather than the productive oxidative phosphorylation pathway. This effect is manifested by a high rate of glucose uptake, active glycolysis, and high lactate levels ( 15 ). Tumor cells also use this special metabolic method to obtain energy and materials for building cellular structures, enhancing malignant cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

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DNAAF5 promotes hepatocellular carcinoma malignant progression by recruiting USP39 to improve PFKL protein stability

Liu

Sun

et al. 2022

Front. Oncol.

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PurposesDynein axonemal assembly factor 5 (DNAAF5) is the transcription factor of regulating the cytoskeleton and hydrodynamic protein complex assembly, however, it was not well elucidated in the malignant progression of hepatocellular carcinoma (HCC).MethodsWe investigated the role of DNAAF5 in hepatocellular carcinoma by using multiple groups of clinical tissues combined with data from the TCGA database. Then we overexpressed DNAAF5 in hepatocellular carcinoma tumor tissues, which correlates with poor patient survival outcomes. Furthermore, we constructed stable cell lines of HCC cells to confirm the cancer-promoting effects of DNAAF5 in hepatocellular carcinoma. To explore the mechanisms of DNAAF5, transcriptome sequencing combined with mass spectrometry was also performed, which showed that DNAAF5 affects its downstream signaling pathway by interacting with PFKL and that DNAAF5 regulates PFKL protein stability by recruiting the deubiquitination protein, USP39. To corroborate these findings, the same series of tissue microarrays were used to confirm correlations between DNAAF5 and PFKL expressions. In animal experiments, DNAAF5 also promoted the proliferation of HCC cells.ResultsWe found that DNAAF5 expressions were markedly higher in HCC tissues, compared to the adjacent normal tissues. Increased levels of DNAAF5 were associated with significantly worse prognostic outcomes for HCC patients. Cell function experiments showed that HCC cells of overexpressing DNAAF5 exhibited faster proliferation rates, stronger clone formation abilities and higher drug resistance rates. However, tumor cell proliferation rates and colony formation were significantly decreased after DNAAF5 knockout, accompanied by an increase in sensitivity to sorafenib. In addition, the results of our study showed that DNAAF5 accelerates PFKL protein deubiquitination by recruiting USP39 in HCC cells. Furthermore, The overexpression of DNAAF5 could promote HCC cell proliferation in vivo and in vitro, whereas USP39 knockdown inhibited this effect. Overall, DNAAF5 serves as a scaffold protein to recruit USP39 to form a ternary complex by directly binding the PFKL protein, thereby improving the stability of the latter, which promotes the malignant process of hepatocellular carcinoma.ConclusionsThese findings revealed DNAAF5 was negatively correlated with the prognosis of patients with hepatocellular carcinoma. It underlying mechanism showed that DNAAF5 directly binds PFKL and recruits the deubiquitinated protein (USP39) to improve the stability of the PFKL protein, thus enhancing abnormal glycolysis in HCC cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DNAAF5 promotes hepatocellular carcinoma malignant progression by recruiting USP39 to improve PFKL protein stability

Liu

Sun

et al. 2022

Front. Oncol.

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“…Snail1 is rapidly degraded in the cells and with a short half-life, due to the continuous ubiquitination and degradation by the proteasome (Brabletz et al, 2021). Several E3 ligases, including FBXL14, FBW7, β-TrCP, and FBXO11, have been shown to promote Snail1 ubiquitination and degradation (Chen et al, 2021;Díaz & de Herreros, 2016;Huang, 2010;Zheng et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Snail1 is rapidly degraded in the cells and with a short half‐life, due to the continuous ubiquitination and degradation by the proteasome (Brabletz et al, 2021). Several E3 ligases, including FBXL14, FBW7, β‐TrCP, and FBXO11, have been shown to promote Snail1 ubiquitination and degradation (Chen et al, 2021; Díaz & de Herreros, 2016; Huang, 2010; Zheng et al, 2014). On the other hand, protein deubiquitination, a process in which ubiquitin is removed from target proteins by deubiquitinases (DUBs), plays an important role in cancer progression including proliferation and metastasis in various tumors (Mennerich et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Deubiquitinating enzyme USP9X regulates metastasis and chemoresistance in triple‐negative breast cancer by stabilizing Snail1

Guan

Yang

Liang

et al. 2022

Journal Cellular Physiology

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Breast cancer is one of the most common malignancies in women worldwide. Triple‐negative breast cancer (TNBC) is a highly aggressive and metastatic subtype that has the characteristics of easy recurrence, poor prognosis as well as lack of targeted therapeutics. Snail1, a key factor regulating epithelial–mesenchymal transition (EMT) process, contributing to metastasis and chemoresistance in human cancers. However, the molecular mechanism of Snail1 stabilization in cancers is not fully understood. Here, we demonstrate that the deubiquitinating enzyme USP9X deubiquitinates and stabilizes Snail1, thereby promoting metastasis and chemoresistance. The depletion and pharmacological inhibition of USP9X by WP1130, an inhibitor of USP9X, downregulate endogenous Snail1 protein, inhibit cell migration, invasion, metastasis, and increase cellular sensitivity to cisplatin and paclitaxel both in vitro and in vivo, whereas the reconstitution of Snail1 in cells with USP9X depletion at least partially reverses these phenotypes. Overall, our study establishes the USP9X‐Snail1 axis as an important regulatory mechanism of breast cancer metastasis and chemoresistance and provides a rationale for potential therapeutic interventions in the treatment of TNBC.

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“…Nucleolar and coiled-body phosphoprotein 1 (NOLC1), a phosphoprotein, consists of a unique central repeat domain, and C-terminal and N-terminal domains [6][7][8]. Huang et al reported that NOLC1 was positively correlated with the tumorigenesis of non-small cell lung cancer (NSCLC) and might be utilized as biomarkers for the early diagnosis of NSCLC [9].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of NOLC1 Inhibits PI3K-AKT Pathway to Improve the Poor Prognosis of Esophageal Carcinoma

Kong

Shang

Diao

et al. 2021

Journal of Oncology

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Objective. Esophageal carcinoma (ESCA) is a common malignant gastrointestinal tumor. The abnormal expression of NOLC1 is involved in the tumorigenesis of various human tumors, whereas the function and mechanism of NOLC1 in ESCA remain unclear. In this study, we explored the relationship between NOLC1 and poor prognosis of ESCA, and its role and mechanism in the occurrence of ESCA. Methods. The NOLC1 expression in ESCA tissues and cell lines was determined by qRT-PCR, immunohistochemistry, or western blot. The Kaplan–Meier method was conducted to estimate the overall survival. Cox regression analysis was carried out to examine the association between patient characteristics and prognosis. A recombined lentiviral vector containing NOLC1 was applied for transfecting ESCA cells (Eca109 and TE-13) and established a stable cell line with low NOLC1 expression or high NOLC1 expression, in the absence or presence of PI3K inhibitor (LY294002) treatment. Cell proliferation, apoptosis rate, invasion ability, migration ability, and PI3K/AKT pathway were detected by CCK8 assay, flow cytometry, Transwell assay, wound-healing assay, and western blot. Results. NOLC1 overexpression was observed in ESCA tissues and ESCA cell lines (EC9706, Eca109, TE-13, Kyse170, T.TN) compared with adjacent normal tissues and normal esophageal cell line HEEC. NOLC1 overexpression was markedly associated with bigger tumor size, lymph node metastasis, and advanced TNM stage. Patients with NOLC1 overexpression have shorter overall survival than that of those with low NOLC1 expression. NOLC1 overexpression was considered to be an independent poor prognostic factor affecting overall survival. NOLC1 knockdown inhibited proliferation, migration, invasion, and cyclin B1 expression and promoted the apoptosis and cleaved-caspase-3 expression of Eca109 and TE-13 cells. NOLC1 overexpression accelerated proliferation, migration, invasion, and cyclin B1 expression and inhibited the apoptosis and cleaved-caspase-3 expression of ESCA cells via activating PI3K/AKT pathway. Rescue experiments showed that PI3K inhibitor (LY294002) could reverse the phenomenon caused by NOLC1 overexpression. Conclusion. NOLC1 may be a marker for poor prognosis. It can participate in the occurrence and development of ESCA via the PI3K/AKT pathway.

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Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

Cited by 43 publications

References 100 publications

DNAAF5 promotes hepatocellular carcinoma malignant progression by recruiting USP39 to improve PFKL protein stability

DNAAF5 promotes hepatocellular carcinoma malignant progression by recruiting USP39 to improve PFKL protein stability

Deubiquitinating enzyme USP9X regulates metastasis and chemoresistance in triple‐negative breast cancer by stabilizing Snail1

Knockdown of NOLC1 Inhibits PI3K-AKT Pathway to Improve the Poor Prognosis of Esophageal Carcinoma

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