Distant metastasis is the main cause of breast cancer-related death; however, effective therapeutic strategies targeting metastasis are still scarce. This is largely attributable to the spatiotemporal intratumor heterogeneity during metastasis. Here we show that protein deacetylase SIRT7 is significantly downregulated in breast cancer lung metastases in human and mice, and predicts metastasis-free survival. SIRT7 deficiency promotes breast cancer cell metastasis, while temporal expression of Sirt7 inhibits metastasis in polyomavirus middle T antigen breast cancer model. Mechanistically, SIRT7 deacetylates and promotes SMAD4 degradation mediated by β-TrCP1, and SIRT7 deficiency activates transforming growth factor-β signaling and enhances epithelial-to-mesenchymal transition. Significantly, resveratrol activates SIRT7 deacetylase activity, inhibits breast cancer lung metastases, and increases survival. Our data highlight SIRT7 as a modulator of transforming growth factor-β signaling and suppressor of breast cancer metastasis, meanwhile providing an effective anti-metastatic therapeutic strategy.
Vascular dysfunction is a typical characteristic of aging, but its contributing roles to systemic aging and the therapeutic potential are lacking experimental evidence. Here, we generated a knock-in mouse model with the causative Hutchinson-Gilford progeria syndrome (HGPS) LmnaG609G mutation, called progerin. The Lmnaf/f;TC mice with progerin expression induced by Tie2-Cre exhibit defective microvasculature and neovascularization, accelerated aging, and shortened life span. Single-cell transcriptomic analysis of murine lung endothelial cells revealed a substantial up-regulation of inflammatory response. Molecularly, progerin interacts and destabilizes deacylase Sirt7; ectopic expression of Sirt7 alleviates the inflammatory response caused by progerin in endothelial cells. Vascular endothelium–targeted Sirt7 gene therapy, driven by an ICAM2 promoter, improves neovascularization, ameliorates aging features, and extends life span in Lmnaf/f;TC mice. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction.
Human clear cell renal cell carcinoma (ccRCC) is the most common solid lesion within kidney, and its prognostic is influenced by the progression covering a complex network of gene interactions. In our study, we screened differential expressed genes, and constructed protein-protein interaction (PPI) network and a weighted gene co-expression network to identify key genes and pathways associated with the progression of ccRCC (n = 56). Functional and pathway enrichment analysis demonstrated that upregulated differentially expressed genes (DEGs) were significantly enriched in response to wounding, positive regulation of immune system process, leukocyte activation, immune response and cell activation. Downregulated DEGs were significantly enriched in oxidation reduction, monovalent inorganic cation transport, ion transport, excretion and anion transport. In the PPI network, top 10 hub genes were identified (TOP2A, MYC, ALB, CDK1, VEGFA, MMP9, PTPRC, CASR, EGFR and PTGS2). In co-expression network, 6 ccRCC-related modules were identified. They were associated with immune response, metabolic process, cell cycle regulation, angiogenesis and ion transport. In conclusion, our study illustrated the hub genes and pathways involved in the progress of ccRCC, and further molecular biological experiments are needed to confirm the function of the candidate biomarkers in human ccRCC.
Human bladder cancer (BCa) is one of the worldwide cancers in men and women populations, with the etiology and mechanism unknown. In our study, we constructed a weighted gene co-expression network to identify gene modules associated with the progression of BCa (n = 93). In the significant module (R2 = 0.48), a total of 103 network hub genes were identified, and 4 of them were hub nodes in the protein-protein interaction network as well. In validation, COL3A1 showed a higher correlation with the disease progression than any other hub genes in hub module in the test set (p < 0.001). Functional and pathway enrichment analysis demonstrated that COL3A1 is overrepresented in pathway of focal adhesion, which associated with tumor progression and might cause metastasis. Gene set enrichment analysis (GSEA) also demonstrated that the gene set of “MAPK signaling pathway” and focal adhesion related pathways were enriched in BCa samples with COL3A1 highly expressed (FDR < 0.05). Considering the clinicopathological parameters, highly-expressed COL3A1 was closely correlated with local recurrence and BCa stage. Survival analysis revealed that BCa patients with higher expression of COL3A1 had a significantly shorter overall survival time and disease free survival time.In conclusion, based on the co-expression analysis, COL3A1 was identified in the association with progression and prognosis of BCa, which might refer a poor prognosisprobably by regulating MAPK signaling pathway.
The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR in human and mouse cells. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair in humans and mice.
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