Acetylation regulates ribonucleotide reductase activity and cancer cell growth

Guo, Chen; Luo, Yin; Warncke, Kurt; Sun, Yao; Yu, David S.; Fu, Haian; Behera, Madhusmita; Ramalingam, Suresh S.; Doetsch, Paul W.; Duong, Duc M.; Lammers, Michael; Curran, Walter J.; Deng, Xingming

doi:10.1038/s41467-019-11214-9

Cited by 57 publications

(52 citation statements)

References 68 publications

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“…In addition to MCM2-7 complex, other proteins in the cluster also in uenced the growth and division of tumor cells by participating in the cell cycle such as RRM2, PRKAR2B, and MKI67. [21][22][23] Most DEPs related to the cell cycle were up-regulated, which was consistent with the vigorous growth and division of tumor cells. The 69 DEPs were involved not only in the cell cycle, but also in cell metabolism ( Figure 3A, B).…”

Section: Discussionsupporting

confidence: 63%

Development of Prognostic Signature Based on Pan-cancer Proteomics

Huang

Weng

Xiang

et al. 2020

Preprint

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Background: Utilizing genomic data to predict cancer prognosis was insufficient. Proteomics can improve our understanding of the etiology and progression of cancer and improve the assessment of cancer prognosis. Based on CPTAC (Clinical Proteomic Tumor Analysis Consortium) which has generated extensive proteomics data of the vast majority of tumors, we can perform a proteomic pan-carcinoma analysis.Methods: The proteomics data and clinical features of cancer patients were collected from CPTAC. We screened 69 differentially expressed proteins with R software. GO and KEGG analysis were performed to clarify the function of these proteins. The DEPs-based prognostic model was identified by least absolute shrinkage and selection operator (LASSO)-Cox regression model. The time-dependent receiver operating characteristics analysis was used to evaluate the ability of the prognostic model to predict overall survival.Results: A total of 69 differentially expressed proteins were screened in five different types of cancers: hepatocellular carcinoma (HCC), lung adenocarcinoma (LUAD), children's brain tumor tissue consortium (CBTTC), clear cell renal cell carcinoma (CCRC) and uterine corpus endometrial carcinoma (UCEC). Furthermore, the differentially expressed proteins were related to cell metabolism, cell proliferation and extracellular matrix. Then 24 DEPs-based classifiers for predicting OS was developed by LASSO-Cox regression model in training cohort, which was validated in validation cohort. Conclusions: In the present study, we identified DEPs-based survival-predictor model to predict most cancers. We are the first group to utilize proteomics to construct a pan-cancer prognosis model, which could accurately and effectively predict the survival rate of most cancers.

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Section: Discussionsupporting

confidence: 63%

Development of Prognostic Signature Based on Pan-cancer Proteomics

Huang

Weng

Xiang

et al. 2020

Preprint

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“…Whether sorafenib promotes RRM2 degradation through this pathway warrants further investigations. Recently, RRM2 acetylation has been shown to regulate RR activity [72]. Acetylation of RRM2 at Lys95 by lysine acetyltransferase 7 (KAT7) disrupts RRM2 homodimerization and inactivates RR.…”

Section: Discussionmentioning

confidence: 99%

“…Acetylation of RRM2 at Lys95 by lysine acetyltransferase 7 (KAT7) disrupts RRM2 homodimerization and inactivates RR. On the other hand, sirtuin 2 (SIRT2) deacetylases RRM2, leading to RR activation [72]. It is possible that the HDAC-inhibitory activity of sorafenib also results in the acetylation of RRM2, then reducing its protein stability.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells

Yang

Liu

2020

Biomolecules

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The main curative treatments for hepatocellular carcinoma (HCC) are surgical resection and liver transplantation, which only benefits 15% to 25% of patients. In addition, HCC is highly refractory and resistant to cytotoxic chemotherapy. Although several multi-kinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, have been approved for treating advanced HCC, only a short increase of median overall survival in HCC patients was achieved. Therefore, there is an urgent need to design more effective strategies for advanced HCC patients. Human ribonucleotide reductase is responsible for the conversion of ribonucleoside diphosphate to 2′-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. In this study, mining the cancer genomics and proteomics data revealed that ribonucleotide reductase regulatory subunit M2 (RRM2) serves as a prognosis biomarker and a therapeutic target for HCC. The RNA sequencing (RNA-Seq) analysis and public microarray data mining found that RRM2 was a novel molecular target of sorafenib in HCC cells. In vitro experiments validated that sorafenib inhibits RRM2 expression in HCC cells, which is positively associated with the anticancer activity of sorafenib. Although both RRM2 knockdown and sorafenib induced autophagy in HCC cells, restoration of RRM2 expression did not rescue HCC cells from sorafenib-induced autophagy and growth inhibition. However, long-term colony formation assay indicated that RRM2 overexpression partially rescues HCC cells from the cytotoxicity of sorafenib. Therefore, this study identifies that RRM2 is a novel target of sorafenib, partially contributing to its anticancer activity in HCC cells.

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“…Deacetylation assay was performed as described. 64 Briefly, the acetylated, Flag-tagged b-catenin protein on agarose beads was incubated with recombinant human glutathione S-transferase-tagged SIRT2 protein (2 mg) (Active Motif, Carlsbad, CA) in deacetylation buffer (50-mM Tris-HCL pH 8.0, 150-mM NaCl, 1-mM MgCl 2 , 5-mM NAD þ ) at 30 C for 3 hours. The reaction was stopped with sodium dodecyl sulfate (SDS) sample buffer, subjected to SDS-polyacrylamide gel electrophoresis, and analyzed by Western blot with acetylated-lysine antibody.…”

Section: In Vitro Deacetylation Assaymentioning

confidence: 99%

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation

Zhou

Rychahou

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Using complementary approaches (intestinal epithelial cell lines, intestinal organoids and SIRT2 knockout mice), we demonstrated that SIRT2, decreased in intestinal tissues from patients with inflammatory bowel diseases, contributes to the maintenance of intestinal epithelium homeostasis through regulation of Wnt-b-catenin signaling. BACKGROUND AND AIMS: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetylase, in intestinal epithelial cell (IEC) proliferation and differentiation and the mechanism by which SIRT2 contributes to maintenance of intestinal cell homeostasis. METHODS: IECs were collected from SIRT2-deficient mice and patients with IBD. Expression of SIRT2, differentiation markers (mucin2, intestinal alkaline phosphatase, villin, Na,K-ATPase, and lysozyme) and Wnt target genes (EPHB2, AXIN2, and cyclin D1) was determined by western blot, real-time RT-PCR, or immunohistochemical (IHC) staining. IECs were treated with TNF or transfected with siRNA targeting SIRT2. Proliferation was determined by villus height and crypt depth, and Ki67 and cyclin D1 IHC staining. For studies using organoids, intestinal crypts were isolated. RESULTS: Increased SIRT2 expression was localized to the more differentiated region of the intestine. In contrast, SIRT2 deficiency impaired proliferation and differentiation and altered stemness in the small intestinal epithelium ex vivo and in vivo. SIRT2-deficient mice showed decreased intestinal enterocyte and goblet cell differentiation but increased the Paneth cell lineage and increased proliferation of IECs. Moreover, we found that SIRT2 inhibits Wnt/b-catenin signaling, which critically regulates IEC proliferation and differentiation. Consistent with a distinct role for SIRT2 in maintenance of gut homeostasis, intestinal mucosa from IBD patients exhibited decreased SIRT2 expression. CONCLUSION: We demonstrate that SIRT2, which is decreased in intestinal tissues from IBD patients, regulates Wnt-b-catenin signaling and is important for maintenance of IEC proliferation and differentiation.

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Acetylation regulates ribonucleotide reductase activity and cancer cell growth

Cited by 57 publications

References 68 publications

Development of Prognostic Signature Based on Pan-cancer Proteomics

Development of Prognostic Signature Based on Pan-cancer Proteomics

Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation

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