Prediction of drug-target binding affinity based on deep learning models.

The prediction of drug-target binding affinity (DTA) plays an important role in drug discovery. Computerized virtual screening techniques have been used for DTA prediction, greatly reducing the time and economic costs of drug discovery. However, these techniques have not succeeded in reversing the low success rate of new drug development. In recent years, the continuous development of deep learning (DL) technology has brought new opportunities for drug discovery through the DTA prediction. This shift has moved the prediction of DTA from traditional machine learning methods to DL. The DL frameworks used for DTA prediction include convolutional neural networks (CNN), graph convolutional neural networks (GCN), and recurrent neural networks (RNN), and reinforcement learning (RL), among others. This review article summarizes the available literature on DTA prediction using DL models, including DTA quantification metrics and datasets, and DL algorithms used for DTA prediction (including input representation of models, neural network frameworks, valuation indicators, and model interpretability). In addition, the opportunities, challenges, and prospects of the application of DL frameworks for DTA prediction in the field of drug discovery are discussed.

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

THAP3 recruits SMYD3 to OXPHOS genes and epigenetically promotes mitochondrial respiration in hepatocellular carcinoma.

Mitochondria harbor the oxidative phosphorylation (OXPHOS) system to sustain cellular respiration. However, the transcriptional regulation of OXPHOS remains largely unexplored. Through the cancer genome atlas (TCGA) transcriptome analysis, transcription factor THAP domain-containing 3 (THAP3) was found to be strongly associated with OXPHOS gene expression. Mechanistically, THAP3 recruited the histone methyltransferase SET and MYND domain-containing protein 3 (SMYD3) to upregulate H3K4me3 and promote OXPHOS gene expression. The levels of THAP3 and SMYD3 were altered by metabolic cues. They collaboratively supported liver cancer cell proliferation and colony formation. In clinical human liver cancer, both of them were overexpressed. THAP3 positively correlated with OXPHOS gene expression. Together, THAP3 cooperates with SMYD3 to epigenetically upregulate cellular respiration and liver cancer cell proliferation.

Targeting SIRT3 sensitizes glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11.

Glioblastoma (GBM) cells require large amounts of iron for tumor growth and progression, which makes these cells vulnerable to destruction via ferroptosis induction. Mitochondria are critical for iron metabolism and ferroptosis. Sirtuin-3 (SIRT3) is a deacetylase found in mitochondria that regulates mitochondrial quality and function. This study aimed to characterize SIRT3 expression and activity in GBM and investigate the potential therapeutic effects of targeting SIRT3 while also inducing ferroptosis in these cells. We first found that SIRT3 expression was higher in GBM tissues than in normal brain tissues and that SIRT3 protein expression was upregulated during RAS-selective lethal 3 (RSL3)-induced GBM cell ferroptosis. We then observed that inhibition of SIRT3 expression and activity in GBM cells sensitized GBM cells to RSL3-induced ferroptosis both in vitro and in vivo. Mechanistically, SIRT3 inhibition led to ferrous iron and ROS accumulation in the mitochondria, which triggered mitophagy. RNA-Sequencing analysis revealed that upon SIRT3 knockdown in GBM cells, the mitophagy pathway was upregulated and SLC7A11, a critical antagonist of ferroptosis via cellular import of cystine for glutathione (GSH) synthesis, was downregulated. Forced expression of SLC7A11 in GBM cells with SIRT3 knockdown restored cellular cystine uptake and consequently the cellular GSH level, thereby partially rescuing cell viability upon RSL3 treatment. Furthermore, in GBM cells, SIRT3 regulated SLC7A11 transcription through ATF4. Overall, our study results elucidated novel mechanisms underlying the ability of SIRT3 to protect GBM from ferroptosis and provided insight into a potential combinatorial approach of targeting SIRT3 and inducing ferroptosis for GBM treatment.

Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer.

BACKGROUND: The Hippo pathway is crucial in organ size control and tumorigenesis. Dysregulation of the Hippo/YAP axis is commonly observed in gastric cancer, while effective therapeutic targets for the Hippo/YAP axis are lacking. Identification of reliable drug targets and the underlying mechanisms that could inhibit the activity of the Hippo/YAP axis and gastric cancer progression is urgently needed. METHODS: We used several gastric cancer cell lines and xenograft models and performed immunoblotting, qPCR, and in vivo studies to investigate the function of CXCR7 in gastric cancer progression. RESULTS: In our current study, we demonstrate that the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator of the Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through the Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block tumorigenesis in gastric cancer. Molecular studies revealed that the activation of CXCR7 could dephosphorylate YAP and facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assays showed that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates that CXCR7 is both the upstream signalling and downstream target of the Hippo/YAP axis in gastric cancer. CONCLUSION: In general, we identified a novel positive feedback loop between CXCR7 and the Hippo/YAP axis, and blockade of CXCR7 could be a plausible strategy for gastric cancer.

The intrinsic resistance of Fusarium solani to the Fusarium-specific fungicide phenamacril is attributed to the natural variation of both T218S and K376M in myosin5.

Fusarium solani is responsible for causing root rot in various crops, resulting in wilting and eventual demise. Phenamacril, a specific inhibitor of myosin5 protein, has gained recognition as an effective fungicide against a broad spectrum of Fusarium species. It has been officially registered for controlling Fusarium diseases through spray application, root irrigation, and seed dipping. In this study, phenamacril was observed to exhibit negligible inhibitory effects on F. solani causing crop root rot, despite the absence of prior exposure to phenamacril. Considering the high selectivity of phenamacril, this phenomenon was attributed to intrinsic resistance and further investigated for its underlying mechanism. Sequence alignment analysis of myosin5 proteins across different Fusarium species revealed significant differences at positions 218 and 376. Subsequent homology modeling and molecular docking results indicated that substitutions T218S, K376M, and T218S&K376M impaired the binding affinity between phenamacril and myosin5 in F. solani. Mutants carrying these substitutions were generated via site-directed mutagenesis. A phenamacril-sensitivity test showed that the EC50 values of mutants carrying T218S, K376M, and T218S&K376M were reduced by at least 6.13-fold, 9.66-fold, and 761.90-fold respectively compared to the wild-type strain. Fitness testing indicated that mutants carrying K376M or T218S&K376M had reduced sporulation compared to the wild-type strain. Additionally, mutants carrying T218S exhibited an enhanced virulence compared to the wild-type strain. However, there were no significant differences observed in mycelial growth rates between the mutants and the wild-type strain. Thus, the intrinsic differences observed at positions 218 and 376 in myosin5 between F. solani and other Fusarium species are specifically associated with phenamacril resistance. The identification of these resistance-associated positions in myosin5 of F. solani has significantly contributed to the understanding of phenamacril resistance mechanisms, thereby discouraging the use of phenamacril for controlling F. solani.

AMPK activation coupling SENP1-Sirt3 axis protects against acute kidney injury.

Acute kidney injury (AKI) is a critical clinical condition that causes kidney fibrosis, and it currently lacks specific treatment options. In this research, we investigate the role of the SENP1-Sirt3 signaling pathway and its correlation with mitochondrial dysfunction in proximal tubular epithelial cells (PTECs) using folic acid (FA) and ischemia-reperfusion-induced (IRI) AKI models. Our findings reveal that Sirt3 SUMOylation site mutation (Sirt3 KR) or pharmacological stimulation (metformin) protected mice against AKI and subsequent kidney inflammation and fibrosis by decreasing the acetylation level of mitochondrial SOD2, reducing mitochondrial reactive oxygen species (mtROS), and subsequently restoring mitochondrial ATP level, reversing mitochondrial morphology and alleviating cell apoptosis. In addition, AKI in mice was similarly alleviated by reducing mtROS levels using N-acetyl-L-cysteine (NAC) or MitoQ. Metabolomics analysis further demonstrated an increase in antioxidants and metabolic shifts in Sirt3 KR mice during AKI, compared with Sirt3 wild-type (WT) mice. Activation of the AMPK pathway using metformin promoted the SENP1-Sirt3 axis and protected PTECs from apoptosis. Hence, the augmented deSUMOylation of Sirt3 in mitochondria, activated through the metabolism-related AMPK pathway, protects against AKI and subsequently mitigated renal inflammation and fibrosis through Sirt3-SOD2-mtROS, which represents a potential therapeutic target for AKI.

Function of the mdxR gene encoding a novel regulator for carbohydrate metabolism and sporulation in Bacillus subtilis 168.

The mdxR gene located upstream of mdxD, encoding a maltogenic amylase, has been annotated as a member of LacI-type transcriptional regulator in Bacillus subtilis 168 but its function has not been investigated yet. In this study, expression pattern of the mdxR promoter (PmdxR) and effects of mdxR were investigated to elucidate the function of mdxR. Expression of PmdxR was monitored by the ß-galactosidase activity expressed from the PmdxR-lacZ fusion integrated at the amyE locus on the chromosome. The promoter was induced by starch, ß-cyclomaltodextrin, or maltose at early exponential phase and kept expressed until late stationary phase. However, it was repressed by glucose, sucrose, or glycerol, suggesting that it was under catabolite repression. Furthermore, interactions of MdxR and Spo0A to the DNA fragment carrying PmdxR or PmdxD were detected by mobility-shift assay, implying that MdxR was a novel transcription regulator for both genes, which were regulated also by Spo0A. The mdxR mutant impaired the expressions of mdxD and malL (encoding an α-glucosidase); degraded accumulated glycogen slower than the wild type and the mdxD mutant. Both of the mdxR and the mdxD mutants formed more endospores (50.95% and 47.10%) than the wild type (23.90%). Enhanced sporulation by these mutations could be of industrial interest where sporulation or endospores of B. subtilis matters. These results indicate that MdxR functions as a transcriptional regulator for mdxR, mdxD, and other genes in the gene cluster that is related to the maltose/maltodextrin metabolism. MdxR and MdxD are also involved in glycogen metabolism and sporulation, tentatively by modulating the net energy balance in the cell.

Ubiquitous mitochondrial creatine kinase promotes the progression of gastric cancer through a JNK-MAPK/JUN/HK2 axis regulated glycolysis.

BACKGROUND: Ubiquitous mitochondrial creatine kinase (uMtCK) transfers high-energy phosphates from mitochondrially generated ATP to creatine to generate phosphocreatine. uMtCK overexpression has been reported in several malignant tumors, however, the clinical significance and impact of uMtCK in gastric cancer (GC) has not been comprehensively studied. METHODS: We first examined uMtCK expression in GC by quantitative real-time PCR and western blot assays. Then the clinicopathological significance of aberrant uMtCK expression was determined by immunohistochemical staining in a GC tissue microarray. Kaplan-Meier analysis was used for survival analysis. The biological functions of uMtCK in GC cells were explored by wound-healing, transwell assays and glucose metabolism assays in vitro as well as a liver metastasis model by spleen injection in nude mice in vivo. RESULTS: We verified that the expression of uMtCK was substantially elevated in GC tissues, significantly associating with a poorer prognosis in GC patients, especially for those with advanced stage. In univariate and multivariate analyses, uMtCK expression emerged as an independent prognostic factor for both disease-free survival and overall survival. Functionally, we demonstrated that uMtCK promoted glycolysis in GC cells and facilitated their migration, invasion and liver metastasis in vitro and in vivo. Mechanistically, uMtCK enhanced GC progression in a HK2-dependent glycolysis via acting the JNK-MAPK/JUN signaling pathway. CONCLUSIONS: uMtCK could serve as a novel independent prognostic biomarker as well as potential therapeutic target for GC patients, particularly for GC patients with an advanced UICC stage and tumor recurrence.

In2Se3, In2Te3, and In2(Se,Te)3 Alloys as Photovoltaic Materials.

In its lowest-energy three-dimensional (3D) hexagonal crystal structure (γ phase), In2Se3 has a direct band gap of ∼1.8 eV and displays high absorption coefficient, making it a promising semiconductor material for optoelectronics. Incorporation of Te allows for tuning the band gap, adding flexibility to device design and extending the application range. Here we report results of hybrid density functional theory calculations to assess the electronic and optical properties of γ-In2Se3, γ-In2Te3, and γ-In2(Se1-xTex)3 alloys, and initial experiments on the growth and characterization of γ-In2Se3 thin films. The predicted band gap of 1.84 eV for γ-In2Se3 is in good agreement with the absorption onset derived from transmission and reflection spectra of thin films. We show that incorporation of Te gives γ-In2(Se1-xTex)3 alloys with a band gap ranging from 1.84 eV down to 1.23 eV, thus covering the optimal band gap range for single-junction solar cells. In addition, the γ-In2Se3/γ-In2(Se1-xTex)3 bilayer could be employed in tandem solar-cell architectures absorbing at Eg ≈ 1.8 eV and at Eg ≤ 1.4 eV, toward overcoming the ∼33% efficiency set by the Shockley-Queisser limit for single junction solar cells. We also discuss band gap bowing and mixing enthalpies, aiming at adding γ-In2Se3, γ-In2Te3, and γ-In2(Se1-xTex)3 alloys to the available toolbox of materials for solar cells and other optoelectronic applications.

Intravascular optical coherence elastography.

Optical coherence elastography (OCE), a functional extension of optical coherence tomography (OCT), visualizes tissue strain to deduce the tissue's biomechanical properties. In this study, we demonstrate intravascular OCE using a 1.1 mm motorized catheter and a 1.6 MHz Fourier domain mode-locked OCT system. We induced an intraluminal pressure change by varying the infusion rate from the proximal end of the catheter. We analysed the pixel-matched phase change between two different frames to yield the radial strain. Imaging experiments were carried out in a phantom and in human coronary arteries in vitro. At an imaging speed of 3019 frames/s, we were able to capture the dynamic strain. Stiff inclusions in the phantom and calcification in atherosclerotic plaques are associated with low strain values and can be distinguished from the surrounding soft material, which exhibits elevated strain. For the first time, circumferential intravascular OCE images are provided side by side with conventional OCT images, simultaneously mapping both the tissue structure and stiffness.

OTUB1 suppresses Hippo signaling via modulating YAP protein in gastric cancer.

Gastric cancer is one of the most lethal human malignancies in the world. Although great efforts are put in developing novel therapeutic targets, the effective targeting drugs are still limited. Recent studies reveal the abnormality of Hippo/YAP axis play critical role in the oncogenic process of gastric cancer. It is of great importance to demonstrate the regulation of Hippo signaling activity and YAP protein turnover in gastric cancer. Besides, the phosphorylation cascade on YAP function, which has been thoroughly investigated, the ubiquitination of YAP is also important in Hippo signaling status. Here, We utilized the DUB (Deubiquitinase) siRNA library to identify critical DUB for Hippo signaling. We discovered OTUB1 as a critical factor to facilitate gastric cancer cell stemness and progression, which deubiquitinated and stabilized YAP protein. The clinical data analysis implicated OTUB1 was higher expressed in gastric cancer, which correlated with YAP activity and poor survival. OUTB1 interacted with YAP protein via its OTU domain (Ovarian tumor domain) and deubiquitinated YAP at several lysine sites (K90, K280, K343, K494 and K497), which subsequently inhibited YAP degradation. Our study revealed a novel deubiquitinase of Hippo/YAP axis and one possible therapeutic target for YAP-driven gastric cancer.

Effect of Precipitates on the Mechanical Performance of 7005 Aluminum Alloy Plates.

In this study, the strength, elongation, and fatigue properties of 7005 aluminum alloy plates with different configurations of precipitates were investigated by means of tensile tests, fatigue tests, and microstructural observation. We found that the number and size of GP zones in an alloy plate matrix increased and the distribution was more uniform after the aging time was extended from 1 h to 4 h at 120 °C, which led to a rise in both strength and elongation of alloy plates with the extending aging time. The fatigue life of the alloy plates shortened slightly at first, then significantly prolonged, and then shortened again with the aging time extending from 1 h to 192 h and a fatigue stress level of 185 MPa and stress ratio (R) = 0. After aging at 120 °C for 96 h, the precipitates in the alloy plate matrix were almost all metastable η'-phase particles, which had the optimal aging strengthening effect on the alloy matrix, and the degree of mismatch between the α-Al matrix and second-phase particles was the smallest; the fatigue crack initiation and propagation resistances were the largest, leading to the best fatigue performance of alloy plates, and the fatigue life of the aluminum plate was the longest, up to 1.272 × 106 cycles. When the aging time at 120 °C was extended to 192 h, there were a small number of equilibrium η phases in the aluminum plates that were completely incoherent with the matrix and destroyed the continuity of the aluminum matrix, easily causing stress concentration. As a result, the fatigue life of alloy plates was shortened to 9.422 × 105 cycles.

Phosphorylation by GSK-3ß increases the stability of SIRT6 to alleviate TGF-ß-induced fibrotic response in renal tubular cells.

AIMS: The deacetylase Sirtuin 6 (SIRT6) is up-regulated during fibrogenesis in renal tubular cells and post-ischemia/reperfusion kidneys. Hence, our aim was to investigate the mechanism of SIRT6 up-regulation upon profibrotic stress. MAIN METHODS: Immunohistochemical staining was used to detect the expression of UBC9 in the kidney section. The interaction of GSK-3ß and SIRT6, and phosphorylation level of SIRT6 were detected by the immunoprecipitation assay. The wild-type and phosphorylated site mutant plasmids of SIRT6 were constructed and stably transfected to BUMPT cells to evaluate the phosphorylation function of SIRT6 by immunoblotting assay. KEY FINDINGS: The phosphorylation of SIRT6 is significantly increased during TGF-ß treatment in mouse renal tubular cells. GSK-3ß can physically interact with SIRT6 in renal tubular cells, and this interaction is enhanced by TGF-ß treatment. Moreover, GSK-3ß is the phosphorylation kinase for SIRT6, and phosphorylates SIRT6 at Serine 326 residue to prevent its ubiquitination-mediated proteasomal degradation. Non-phosphorylatable mutant, S326A, of SIRT6, restores ß-catenin activation and fibrotic changes in renal tubular cells. SIGNIFICANCE: The present study demonstrates that a new mechanism for GSK-3ß-mediated anti-fibrotic function in renal fibrosis through phosphorylation of SIRT6 to prevent its proteasomal degradation.

COVID-19 metabolism: Mechanisms and therapeutic targets.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dysregulates antiviral signaling, immune response, and cell metabolism in human body. Viral genome and proteins hijack host metabolic network to support viral biogenesis and propagation. However, the regulatory mechanism of SARS-CoV-2-induced metabolic dysfunction has not been elucidated until recently. Multiomic studies of coronavirus disease 2019 (COVID-19) revealed an intensive interaction between host metabolic regulators and viral proteins. SARS-CoV-2 deregulated cellular metabolism in blood, intestine, liver, pancreas, fat, and immune cells. Host metabolism supported almost every stage of viral lifecycle. Strikingly, viral proteins were found to interact with metabolic enzymes in different cellular compartments. Biochemical and genetic assays also identified key regulatory nodes and metabolic dependencies of viral replication. Of note, cholesterol metabolism, lipid metabolism, and glucose metabolism are broadly involved in viral lifecycle. Here, we summarized the current understanding of the hallmarks of COVID-19 metabolism. SARS-CoV-2 infection remodels host cell metabolism, which in turn modulates viral biogenesis and replication. Remodeling of host metabolism creates metabolic vulnerability of SARS-CoV-2 replication, which could be explored to uncover new therapeutic targets. The efficacy of metabolic inhibitors against COVID-19 is under investigation in several clinical trials. Ultimately, the knowledge of SARS-CoV-2-induced metabolic reprogramming would accelerate drug repurposing or screening to combat the COVID-19 pandemic.

Portevin-Le Chatelier Characterization of Quenched Al-Mg Alloy Sheet with Different Mg Concentrations.

In the present study, the PLC characteristic parameters and DSA mechanism of Al-(2.86~9.41) Mg alloy sheets were investigated during tensile testing at room temperature with a tensile rate of 1 × 10-3 s-1. On the basis of the solution Mg concentrations in the α-Al matrix, the initial vacancy concentration, the second-phase particle configuration and the recrystallized grain configuration are almost the same by quenching treatment. The results show that the type of room-temperature tensile stress-strain curves of quenched Al-(2.86~9.41) Mg alloy sheets varied according to the Mg content. The type of stress-strain curve of the Al-2.86 Mg alloy sheet was B + C, while the type of stress-strain curve of the Al-(4.23~9.41) Mg alloy sheets was C. When the quenched Al-(2.86~9.41) Mg alloy sheets were stretched at room temperature, the strain cycle of the rectangular waves corresponding to the high stress flow ΔεTmax and stress drop amplitude Δσ on the zigzag stress-strain curve of alloy sheets increased with increasing the Mg content. Moreover, the strain cycle of ΔεTmax and Δσ on the stress-strain curve of alloy sheets increased gradually with increasing tensile deformation. The yield stress of quenched Al-(2.86~9.41) Mg alloy sheets increased gradually with increasing the Mg content. Moreover, the critical strain corresponding to yield stress εσ and the critical strain corresponding to the occurrence of the PLC shearing band εc of alloy sheets both increased with increasing the Mg content. However, the difference in flow strain value Δεc-σ between εc and εσ of alloy sheets decreased gradually with increasing the Mg content.

Erratum: Spectroscopic thermo-elastic optical coherence tomography for tissue characterization: publisher's note.

[This corrects the article on p. 1430 in vol. 13, PMID: 35414978.].

DUB1 suppresses Hippo signaling by modulating TAZ protein expression in gastric cancer.

BACKGROUND: The Hippo pathway functions as a tumor suppressor pathway in human cancers, while dysfunction of the Hippo pathway is frequently observed in malignancies. Although YAP/TAZ activity is tightly controlled by the phosphorylation cascade of the MST-LATS-YAP/TAZ axis, it is still unclear why the YAP/TAZ proteins are activated in human cancers despite Hippo pathway activation. Recent studies have suggested that in addition to phosphorylation, several other posttranslational modifications, including ubiquitination, also play critical roles in modulating TAZ function. METHODS: We used several gastric cancer cell lines and performed western blot analysis, real-time PCR, immunoprecipitation assays, and in vitro ubiquitination assays and established a xenograft mouse model. RESULTS: Here, by screening a DUB (deubiquitinase) siRNA library, we discovered that DUB1 functions as a critical modulator that facilitates gastric cancer stemness and progression by deubiquitinating and activating the TAZ protein. We also found that DUB1 expression was elevated in gastric cancer and that elevated DUB1 expression correlated with TAZ activation and poor survival. DUB1 associates with the TAZ protein and deubiquitinates TAZ at several lysine residues, which subsequently stabilizes TAZ and facilitates its function. CONCLUSIONS: Our study revealed a novel deubiquitinase in the Hippo/TAZ axis and identified one possible therapeutic target for Hippo-driven gastric cancer.

Mitotic SENP3 activation couples with cGAS signaling in tumor cells to stimulate anti-tumor immunity.

Our previous studies show that the mitotic phosphorylation of SUMO-specific protease 3 (SENP3) can inhibit its de-SUMOylation activity in G2/M phase of the cell cycle. Inhibition of SENP3 plays a critical role in the correct separation of sister chromatids in mitosis. The mutation of mitotic SENP3 phosphorylation causes chromosome instability and promotes tumorigenesis. In this study, we find that the mutation of mitotic SENP3 phosphorylation in tumor cells can suppress tumor growth in immune-competent mouse model. We further detect an increase of CD8+ T cell infiltration in the tumors, which is essential for the anti-tumor effect in immune-competent mouse model. Moreover, we find that mitotic SENP3 activation increases micronuclei formation, which can activate cGAS signaling-dependent innate immune response. We confirmed that cGAS signaling mediates the mitotic SENP3 activation-induced anti-tumor immunity. We further show that p53 responding to DNA damage activates mitotic SENP3 by inhibiting phosphorylation, and further increases cellular senescence as well as the related innate immune response in tumor cells. Furthermore, TCGA database demonstrates that the SENP3 expression positively correlates with the induction of innate immune response as well as the survival of the p53 mutant pancreatic cancer patients. Together, these data reveal that mitotic SENP3 activation in tumor cells can promote host anti-tumor immune response by coupling with cGAS signaling.