BACKGROUND: Cisplatin-based chemoresistance is major obstacle for breast cancer (BC) including Triple-negative breast cancer (TNBC). SIRT7 is reportedly involved in the progression of BC, the underlining mechanism in Cisplatin-based chemoresistance in BC remains unclear. This work is to elucidate effects of SIRT7 on cisplatin resistance in breast cancer regulated by miR-152-3p.
METHODS: The RNA expression of SIRT7 and miRNAs in breast cancer were available from TCGA database. SIRT7-targeted miRNAs were predicted by TargetScan, miRanda, miRDB databases. The association of SIRT7 expression with predicted miRNA was validated by Luciferase assay. Cell apoptosis was determined by Flow cytometry. Cell viability was detected by CCK8 assay. The mRNA expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Protein expression was determined by Western blotting assay.
RESULTS: SIRT7 mRNA levels were dramatically enhanced in BC tissues compared to para-carcinoma tissues, also increased in BC patients with Cisplatin-based chemotherapy containing TNBC compared with those without. The increase of SIRT7 expression was obviously relevant to shorter survive time of them. Importantly, SIRT7 inhibition facilitated Cisplatin-induced cell apoptosis of TNBC (MDA-MB-231 and MDA-MB-468) and non- TNBC (MCF-7). Notably, miR-152-3p was predicted as a negative regulator of SIRT7 by overlapping downregulated miRNAs in BC patients treated with Cisplatin-based chemotherapy and miRNAs to target SIRT7. Mechanically, miR-152-3p blocked SIRT7 to stimulate an activation of FOXO3a, cleaved PARP1 and Caspase-3, sensitizing Cisplatin-induced apoptosis of BC cells.
CONCLUSIONS: Inhibition of SIRT7 by miR-152-3p may be a promising strategy against the resistance to cisplatin-based chemotherapy in BC containing TNBC.

Sirtuins, as NAD+-dependent deacetylases, are widely found in eubacteria, archaea, and eukaryotes, and they play key roles in regulating cellular functions. Among these, SIRT7 stands out as a member discovered relatively late and studied less extensively. It is localized within the nucleus and displays enzymatic activity as an NAD+-dependent deacetylase, targeting a diverse array of acyl groups. The role of SIRT7 in important cellular processes like gene transcription, cellular metabolism, cellular stress responses, and DNA damage repair has been documented in a number of studies conducted recently. These studies have also highlighted SIRT7\'s strong correlation with human diseases like aging, cancer, neurological disorders, and cardiovascular diseases. In addition, a variety of inhibitors against SIRT7 have been reported, indicating that targeting SIRT7 may be a promising strategy for inhibiting tumor growth. The purpose of this review is to thoroughly look into the structure and function of SIRT7 and to explore its potential value in clinical applications, offering an essential reference for research in related domains.

BACKGROUND: Sirtuin 7 (SIRT7) is pivotal in diverse diseases progression. Importantly, SIRT7 is associated with melanin production. However, whether SIRT7 regulates vitiligo is unclear. Therefore, we aimed to investigate the effects of SIRT7 on pigmentation and the modification of glucose 6-phosphate dehydrogenase (G6PD).
METHODS: After knockdown SIRT7 and G6PD, pigmentation of melanocytes was evaluated using commercial kits, immunofluorescence, and Western blot analysis. The succinylation of G6PD mediated by SIRT7 was analyzed using co-immunoprecipitation, immunofluorescence, Western blot analysis, and cycloheximide-chase experiment.
RESULTS: We found that SIRT7 was highly expressed in vitiligo skin lesions. Knockdown of SIRT7 increased tyrosinase activity, melanin content, and the levels of α-melanocyte-stimulating hormone, MITF, TYR, TRP1, and TRP2. Additionally, SIRT7 directly interacted with G6PD. Silenced SIRT7 promoted the succinylation of G6PD and enhanced its protein stability. G6PD knockdown reversed the effect of reduced SIRT7 expression on melanin production.
UNASSIGNED: Silencing of SIRT7 promotes pigmentation of melanocytes by succinylating G6PD, suggesting that SIRT7-mediated G6PD desuccinylation may promote vitiligo progression.

Vascular calcification is frequently seen in patients with chronic kidney disease (CKD), and significantly increases cardiovascular mortality and morbidity. Sirt7, a NAD+-dependent histone deacetylases, plays a crucial role in cardiovascular disease. However, the role of Sirt7 in vascular calcification remains largely unknown. Using in vitro and in vivo models of vascular calcification, this study showed that Sirt7 expression was significantly reduced in calcified arteries from mice administered with high dose of vitamin D3 (vD3). We found that knockdown or inhibition of Sirt7 promoted vascular smooth muscle cell (VSMC), aortic ring and vascular calcification in mice, whereas overexpression of Sirt7 had opposite effects. Intriguingly, this protective effect of Sirt7 on vascular calcification is dependent on its deacetylase activity. Unexpectedly, Sirt7 did not alter the osteogenic transition of VSMCs. However, our RNA-seq and subsequent studies demonstrated that knockdown of Sirt7 in VSMCs resulted in increased intracellular reactive oxygen species (ROS) accumulation, and induced an Nrf-2 mediated oxidative stress response. Treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly attenuated the inhibitory effect of Sirt7 on VSMC calcification. Furthermore, we found that knockdown of Sirt7 delayed cell cycle progression and accelerated cellular senescence of VSMCs. Taken together, our results indicate that Sirt7 regulates vascular calcification at least in part through modulation of ROS and cellular senescence of VSMCs. Sirt7 may be a potential therapeutic target for vascular calcification.

The nucleolar enzyme sirtuin 7 (SIRT7) promotes cancer progression in certain malignancies, likely in part by controlling ribosome biosynthesis. Recently, we discovered that SIRT7 destabilizes the cyclin dependent kinase inhibitor 2A (CDKN2A, known as ARF) within the nucleolus, aiding cancer progression. We propose that targeting nucleolar SIRT7 offers promise for new anti-cancer therapies.

BACKGROUND: Long noncoding RNAs (lncRNAs) play vital regulatory functions in non-small cell lung cancer (NSCLC). Cisplatin (DDP) resistance has significantly decreased the effectiveness of DDP-based chemotherapy in NSCLC patients. This study aimed to investigate the effects of SH3PXD2A antisense RNA 1 (SH3PXD2A-AS1) on DDP resistance in NSCLC.
METHODS: Proliferation and apoptosis of DDP-resistant NSCLC cells were detected using cell counting kit-8 and flow cytometry assays. The interaction between SH3PXD2A-AS1 and sirtuin 7 (SIRT7) was assessed using co-immunoprecipitation (Co-IP), RNA pull-down, RNA immunoprecipitation (RIP), RNA fluorescence in situ hybridization, and immunofluorescence assays, while succinylation (SUCC) of Forkhead Box M1 (FOXM1) was analyzed by IP and Western blot assays. The role of SH3PXD2A-AS1 in vivo was explored using a xenografted tumor model.
RESULTS: Expression of SH3PXD2A-AS1 was found elevated in DDP-resistant NSCLC cells, while it\'s knocking down translated into suppression of cell viability and promotion of apoptosis. Moreover, silencing of SH3PXD2A-AS1 resulted in decreased FOXM1 protein level and enhanced FOXM1-SUCC protein level. The SIRT7 was found to interact with FOXM1, translating into inhibition of FOXM1 SUCC at the K259 site in human embryonic kidney (HEK)-293T cells. Overexpressing of SIRT7 reversed the increase of FOXM1-SUCC protein level and apoptosis, and the decrease of cell viability induced by silencing of SH3PXD2A-AS1. In tumor-bearing mice, SH3PXD2A-AS1 inhibition suppressed tumor growth and the protein levels of Ki67, SIRT7, and FOXM1.
CONCLUSIONS: SH3PXD2A-AS1 promoted DDP resistance in NSCLC cells by regulating FOXM1 SUCC via SIRT7, offering a promising therapeutic approach for NSCLC.

Gemcitabine serves as a first-line chemotherapeutic treatment for pancreatic cancer (PC), but it is prone to rapid drug resistance. Increasing the sensitivity of PC to gemcitabine has long been a focus of research. Fasting interventions may augment the effects of chemotherapy and present new options. SIRT7 is known to link metabolism with various cellular processes through post-translational modifications. We found upregulation of SIRT7 in PC cells is associated with poor prognosis and gemcitabine resistance. Cross-analysis of RNA-seq and ATAC-seq data suggested that GLUT3 might be a downstream target gene of SIRT7. Subsequent investigations demonstrated that SIRT7 directly interacts with the enhancer region of GLUT3 to desuccinylate H3K122. Our group\'s another study revealed that GLUT3 can transport gemcitabine in breast cancer cells. Here, we found GLUT3 KD reduces the sensitivity of PC cells to gemcitabine, and SIRT7 KD-associated gemcitabine-sensitizing could be reversed by GLUT3 KD. While fasting mimicking induced upregulation of SIRT7 expression in PC cells, knocking down SIRT7 enhanced sensitivity to gemcitabine through upregulating GLUT3 expression. We further confirmed the effect of SIRT7 deficiency on the sensitivity of gemcitabine under fasting conditions using a mouse xenograft model. In summary, our study demonstrates that SIRT7 can regulate GLUT3 expression by binding to its enhancer and altering H3K122 succinylation levels, thus affecting gemcitabine sensitivity in PC cells. Additionally, combining SIRT7 knockdown with fasting may improve the efficacy of gemcitabine. This unveils a novel mechanism by which SIRT7 influences gemcitabine sensitivity in PC and offer innovative strategies for clinical combination therapy with gemcitabine.

UNASSIGNED: Vitiligo is an autoimmune disease characterized by loss of skin pigmentation and currently has no effective treatment. This study aimed to investigate the function of SIRT7, being an important desuccinylase mediating multiple disease progression, and its mechanism in vitiligo progression.
UNASSIGNED: Normal human melanocytes (NHM) PIG1 and vitiligo human melanocytes (VHM) PIG3V were utilized in this research. The role of sirtuin 7 (SIRT7) and Ezrin (EZR) on melanin synthesis was investigated by detecting tyrosinase activity, melanin content, α-MSH levels, and the protein levels of melanin-related markers. The function of EZR was identified via rescue experiments, while the underlying mechanism was investigated via bioinformatic analysis, co-immunoprecipitation (co-IP), immunoprecipitation (IP), and Western blot techniques.
UNASSIGNED: Results showed that only SIRT7 was highly expressed in vitiligo human melanocytes, where knockingdown SIRT7 translated into increased melanin synthesis in melanocytes. Mechanistically, SIRT7 knockdown promoted the succinylation of EZR at the Lys (K)60 site. Moreover, overexpressing EZR induced higher melanin synthesis in melanocytes, while its knocking down exerted the opposite effect by inhibiting SIRT7 knockdown-induced melanin synthesis.
UNASSIGNED: SIRT7 inhibited melanin synthesis in melanocytes by suppressing the succinylation of EZR. These findings are envisaged to provide a novel theoretical basis for vitiligo treatment.

Mesenchymal stem cells (MSCs) of placental origin hold great promise in tissue engineering and regenerative medicine for diseases affecting cartilage and bone. However, their utility has been limited by their tendency to undergo premature senescence and phenotypic drift into adipocytes. This study aimed to explore the potential involvement of a specific subset of aging and antiaging genes by measuring their expression prior to and following in vitro-induced differentiation of placental MSCs into chondrocytes and osteoblasts as opposed to adipocytes. The targeted genes of interest included the various LMNA/C transcript variants (lamin A, lamin C, and lamin A∆10), sirtuin 7 (SIRT7), and SM22α, along with the classic aging markers plasminogen activator inhibitor 1 (PAI-1), p53, and p16INK4a. MSCs were isolated from the decidua basalis of human term placentas, expanded, and then analyzed for phenotypic properties by flow cytometry and evaluated for colony-forming efficiency. The cells were then induced to differentiate in vitro into chondrocytes, osteocytes, and adipocytes following established protocols. The mRNA expression of the targeted genes was measured by RT-qPCR in the undifferentiated cells and those fully differentiated into the three cellular lineages. Compared to undifferentiated cells, the differentiated chondrocytes demonstrated decreased expression of SIRT7, along with decreased PAI-1, lamin A, and SM22α expression, but the expression of p16INK4a and p53 increased, suggesting their tendency to undergo premature senescence. Interestingly, the cells maintained the expression of lamin C, which indicates that it is the primary lamin variant influencing the mechanoelastic properties of the differentiated cells. Notably, the expression of all targeted genes did not differ from the undifferentiated cells following osteogenic differentiation. On the other hand, the differentiation of the cells into adipocytes was associated with decreased expression of lamin A and PAI-1. The distinct patterns of expression of aging and antiaging genes following in vitro-induced differentiation of MSCs into chondrocytes, osteocytes, and adipocytes potentially reflect specific roles for these genes during and following differentiation in the fully functional cells. Understanding these roles and the network of signaling molecules involved can open opportunities to improve the handling and utility of MSCs as cellular precursors for the treatment of cartilage and bone diseases.

p53 deficiency plays a crucial role in chemotherapy resistance through various biological events, including posttranslational modifications (PTMs). Recently, lysine crotonylation (Kcr) has been shown to play a vital role in cancer progression. However, the global p53-regulated crotonylome and the function of these altered Kcr proteins after p53 deficiency remain unclear. In this study, we used a SILAC-based quantitative crotonylome to identify 3,520 Kcr in 1924 crotonylated proteins in response to p53 knockout. We found that increased crotonylation of RRM2 at K283 (RRM2K283Cr) in the presence of p53 deficiency promoted HCT116 cell resistance to cisplatin. We discovered that SIRT7 could be the decrotonylase of RRM2 and was downregulated after p53 knockout, resulting in increased RRM2K283Cr. Mechanistically, p53 deficiency inhibited cell apoptosis by upregulating RRM2 protein expression and RRM2K283Cr-mediated cleaved-PARP1 and cleaved-caspase3 expression, and SIRT7 was downregulated to upregulate crotonylation of RRM2 upon p53 deficiency. In conclusion, our results indicated that p53 deficiency plays a malignant role in colon cancer resistance to cisplatin therapy by regulating RRM2 protein and RRM2K283Cr expression. Our findings provide a novel therapeutic target against p53-deficient cancer.