ZDHHC1 downregulates LIPG and inhibits colorectal cancer growth via IGF2BP1 Palmitoylation.

Alteration in lipid metabolism is recognized as a hallmark feature of colorectal cancer (CRC). Protein S-palmitoylation plays a critical role in many different cellular processes including protein-lipid interaction. Zinc Finger DHHC-Type Containing 1 (ZDHHC1, also known as ZNF377) belongs to the palmitoyl-transferase ZDHHC family, and is a potential tumor suppressor. However, our knowledge of the functional roles of ZDHHC1 in CRC is limited. We discovered that ZDHHC1 expression was downregulated in CRC tissues and that low levels of ZDHHC1 were associated with unfavorable prognosis. Functional studies showed that ZDHHC1 inhibited CRC cell proliferation and invasion in vitro and in vivo. We also found that lipase G (LIPG) is negatively regulated by ZDHHC1 and plays a key role in CRC cell growth through lipid storage. Additionally, we demonstrated that ZDHHC1 functions as a IGF2BP1-palmitoylating enzyme that induces S-palmitoylation at IGF2BP1-C337, which results in downregulated LIPG expression via m6A modification. Mechanistic investigations revealed that the ZDHHC1/IGF2BP1/LIPG signaling axis is associated with inhibition of CRC cell growth. Our study uncovers the potential role of ZDHHC1 in CRC, including inhibition of CRC growth by reducing the stability of LIPG mRNA in an m6A dependent-manner by palmitoylation of IGF2BP1.

Cell-free Nucleic Acid as Promising Diagnostic Biomarkers for Gastric Cancer: a Systematic Review.

Background: Gastric cancer (GC) is a common malignancy with early detection being crucial for survival. Liquid biopsy analysis using cell-free nucleic acid is a preferred method for detection. Hence, we conducted a systematic review to assess the diagnostic efficacy of cell-free nucleic acid markers for GC. Methods: We searched PubMed and ISI Web of Science databases for articles that conformed to our inclusion and exclusion criteria from 2012 to 2022. The following information was abstracted: first author, year of publication, country/region, age, male proportion, tumor stage for cases, specimen type, measurement method, targeted markers and diagnostic related indicators (including sensitivity, specificity, AUC, P-value). Results: Fifty-eight studies examined cell-free RNAs (cfRNAs) with a total of 62 individual circulating markers and 7 panels in serum or plasma, while 21 studies evaluated cell-free DNAs (cfDNAs) with 29 individual circulating markers and 7 panels. For individual cfRNAs, the median (range) sensitivity and specificity were 80% (21% - 98%) and 80% (54% - 99%), respectively. The median (range) sensitivity and specificity for cfRNA panels were 86% (83% - 90%) and 75% (60% - 98%), respectively. In comparison, the median (range) sensitivity and specificity reported for individual cfDNAs were 50% (18% - 96%) and 93% (57% - 100%), respectively, while cfDNA panels had a median (range) sensitivity and specificity of 85% (41% - 92%) and 73.5% (38% - 90%), respectively. The meta results indicate that cfRNA markers exhibit high sensitivity (80%) and low specificity (80%) for detecting GC, while cfDNA markers have lower sensitivity (59%) but higher specificity (92%). Conclusions: This review has demonstrated that cell-free nucleic acids have the potential to serve as useful diagnostic markers for GC. Given that both cfRNA and cfDNA markers have shown promising diagnostic performance for GC, the combination of the two may potentially enhance diagnostic efficiency.

HMGA2 overexpression activates IGF2BP2 to stabilize APLP2 via m6A modification and promote pancreatic cancer progression.

Pancreatic cancer is a highly aggressive malignancy of the digestive system, with occult onset, rapid progression, and poor prognosis. The genetic heterogeneity of pancreatic cancer contributes to its highly malignant biological behavior. HMGA2 is overexpressed in tumors and is known to regulate tumor progression in various cancers through the HMGA2-IGF2BP2 axis, but its role and mechanism in pancreatic cancer remain unclear. In this study, we demonstrated that HMGA2 promotes pancreatic cancer progression. We further revealed that HMGA2 upregulates IGF2BP2, which stabilizes APLP2 mRNA via m6A modification, thereby promoting pancreatic cancer progression. These results indicate that HMGA2/IGF2BP2/APLP2 signaling axis regulates the progression of pancreatic cancer.

Fumarate Hydratase Enhances the Therapeutic Effect of PD-1 Antibody in Colorectal Cancer by Regulating PCSK9.

Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect.

Method for the extraction of circulating nucleic acids based on MOF reveals cell-free RNA signatures in liver cancer.

Cell-free RNA (cfRNA) allows assessment of health, status, and phenotype of a variety of human organs and is a potential biomarker to non-invasively diagnose numerous diseases. Nevertheless, there is a lack of highly efficient and bias-free cfRNA isolation technologies due to the low abundance and instability of cfRNA. Here, we developed a reproducible and high-efficiency isolation technology for different types of cell-free nucleic acids (containing cfRNA and viral RNA) in serum/plasma based on the inclusion of nucleic acids by metal-organic framework (MOF) materials, which greatly improved the isolation efficiency and was able to preserve RNA integrity compared with the most widely used research kit method. Importantly, the quality of cfRNA extracted by the MOF method is about 10-fold that of the kit method, and the MOF method isolates more than three times as many different RNA types as the kit method. The whole transcriptome mapping characteristics of cfRNA in serum from patients with liver cancer was described and a cfRNA signature with six cfRNAs was identified to diagnose liver cancer with high diagnostic efficiency (area under curve = 0.905 in the independent validation cohort) using this MOF method. Thus, this new MOF isolation technique will advance the field of liquid biopsy, with the potential to diagnose liver cancer.

TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks.

53BP1 promotes nonhomologous end joining (NHEJ) over homologous recombination (HR) repair by mediating inactivation of DNA end resection. Ubiquitination plays an important role in regulating dissociation of 53BP1 from DNA double-strand breaks (DSBs). However, how this process is regulated remains poorly understood. Here, we demonstrate that TRABID deubiquitinase binds to 53BP1 at endogenous level and regulates 53BP1 retention at DSB sites. TRABID deubiquitinates K29-linked polyubiquitination of 53BP1 mediated by E3 ubiquitin ligase SPOP and prevents 53BP1 dissociation from DSBs, consequently inducing HR defects and chromosomal instability. Prostate cancer cells with TRABID overexpression exhibit a high sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Our work shows that TRABID facilitates NHEJ repair over HR during DNA repair by inducing prolonged 53BP1 retention at DSB sites, suggesting that TRABID overexpression may predict HR deficiency and the potential therapeutic use of PARP inhibitors in prostate cancer.

Downregulation of CBX7 induced by EZH2 upregulates FGFR3 expression to reduce sensitivity to cisplatin in bladder cancer.

BACKGROUND: Cisplatin-based cytotoxic chemotherapy is considered to be the first-line therapy for advanced bladder cancer (BC), but resistance to cisplatin limits its antitumor effect. Fibroblast growth factor receptor 3 (FGFR3) has been reported to contribute to the progression and cisplatin resistance of BC. Meanwhile, chromobox protein homologue 7 (CBX7) was reported to inhibit BC progression. And our previous RNA-seq data on CBX7 (GSE185630) suggested that CBX7 might repress FGFR3, but the underlying mechanism and other cancer-related functions of CBX7 are still unknown. METHODS: Silico analysis of RNA-seq data to identify the upstream regulators and downstream target genes of CBX7. The western blot analysis, quantitative real-time PCR (RT-qPCR), chromatin immunoprecipitation (ChIP)-qPCR analysis, CCK-8 assay, and nude mice xenograft models were used to confirm the enhancer of zeste homologue (EZH2)/CBX7/ FGFR3 axis. RESULTS: In this study, we first showed that CBX7 is downregulated in BC. Then, we revealed that EZH2 represses CBX7 expression by increasing H3K27me3 in BC cells. Moreover, we demonstrated that CBX7 directly downregulates FGFR3 expression and sensitises BC cells to cisplatin treatment by inactivating the phosphatidylinositol 3-kinase (PI3K)-(RAC-alpha serine/threonine-protein kinase) AKT signalling pathway. CONCLUSIONS: These results suggest that CBX7 is an ideal candidate to overcome cisplatin resistance in BC.

HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer.

HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Nontargeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglandins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mechanistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sensitivity to genetic or pharmacologic inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5-deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregulation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5-deficient pancreatic cancer patients. SIGNIFICANCE: The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary management as a feasible strategy for treating a subset of patients with pancreatic cancer.

The role of hypoxia-inducible factor-1 alpha in multidrug-resistant breast cancer.

Breast cancer is the most common cancer in women worldwide with increasing incidence. Significant therapeutics advances in the field of breast cancer have resulted in a growing number of treatment options, whereas de novo or acquired resistance is still a persistent clinical challenge. Drug resistance involves a variety of mechanisms, and hypoxia is one of the many causes. Hypoxia-inducible Factor-1 Alpha (HIF-1α) is a key transcription factor which can regulate the response of cells to hypoxia. HIF-1α can trigger anaerobic glycolysis of tumor cells, induce angiogenesis, promote the proliferation, invasion, and migration of tumor cells, and lead to multidrug resistance. This review mainly discusses the role of HIF-1α in the drug-resistant breast cancer and highlighted the potential of HIF-1α -targeted therapy.

CBX3 Regulated By YBX1 Promotes Smoking-induced Pancreatic Cancer Progression via Inhibiting SMURF2 Expression.

As a key reversible and heritable mechanism of transcriptional regulation, the epigenetic modification plays a crucial role in tumorigenesis. Of note, tobacco smoking induces epigenetic modifications to promote pancreatic cancer development. Chromobox protein homolog 3 (CBX3) acts as an epigenetic regulator, modulating gene expression of downstream targets via chromatin modifications. To date, the relationship between CBX3 and smoking in pancreatic cancer remains unknown. This study aimed to uncover the specific role and underlying mechanism of CBX3 in smoking-related pancreatic cancer. The bioinformatics analyses were conducted to identify CBX3 as a key player in tobacco-induced pancreatic cancer. The abnormal upregulation of CBX3 was associated with poor prognosis in pancreatic cancer patients. Moreover, cigarette smoke extract (CSE) exposure promoted the overexpression of Y-box-binding protein 1 (YBX1), which consequently led to upregulated CBX3 in pancreatic cancer cells. We also revealed that CBX3 enhanced pancreatic cancer progression, likely by inhibiting the expression of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) and promoting the activation of TGF-ß signaling. In summary, the YBX1/CBX3/SMURF2 signaling axis may be a promising therapeutic target in patients with smoking-related pancreatic cancer.

Extracellular vesicle biomarkers for pancreatic cancer diagnosis: a systematic review and meta-analysis.

BACKGROUND: Extracellular vesicle (EV) biomarkers have promising diagnosis and screening capacity for several cancers, but the diagnostic value for pancreatic cancer (PC) is controversial. The aim of our study was to review the diagnostic performance of EV biomarkers for PC. METHODS: We performed a systematic review of PubMed, Medline, and Web Of Science databases from inception to 18 Feb 2022. We identified studies reporting the diagnostic performance of EV biomarkers for PC and summarized the information of sensitivity, specificity, area under the curve (AUC), or receiver operator characteristic (ROC) curve) in according to a pre-designed data collection form. Pooled sensitivity and specificity was calculated using a random-effect model. RESULTS: We identified 39 studies, including 2037 PC patients and 1632 noncancerous, seven of which were conducted independent validation tests. Seventeen studies emphasized on EV RNAs, sixteen on EV proteins, and sixteen on biomarker panels. MiR-10b, miR-21, and GPC1 were the most frequently reported RNA and protein for PC diagnosis. For individual RNAs and proteins, the pooled sensitivity and specificity were 79% (95% CI: 77-81%) and 87% (95% CI: 85-89%), 72% (95% CI: 69-74%) and 77% (95% CI: 74-80%), respectively. the pooled sensitivity and specificity of EV RNA combined with protein panels were 84% (95% CI: 81-86%) and 89% (95% CI: 86-91%), respectively. Surprisingly, for early stage (stage I and II) PC EV biomarkers showed excellent diagnostic performance with the sensitivity of 90% (95% CI: 87-93%) and the specificity of 94% (95% CI: 92-95%). Both in sensitivity and subgroup analyses, we did not observe notable difference in pooled sensitivity and specificity. Studies might be limited by the isolation and detection techniques of EVs to a certain extent. CONCLUSIONS: EV biomarkers showed appealing diagnostic preference for PC, especially for early stage PC. Solving the deficiency of technologies of isolation and detection EVs has important implications for application these novel noninvasive biomarkers in clinical practice.

CBX7 represses the POU2F2 to inhibit the PD-L1 expression and regulate the immune response in bladder cancer.

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system worldwide. To date, immune checkpoint inhibitors (including PD-1/PD-L1) have been applied to treat patients with bladder cancer in the clinic and achieved the promising outcome. Further improvement of the anticancer efficiency of these immune therapies is crucial for bladder cancer. Our previous RNA-seq data on CBX7 (GSE185630) suggested that CBX7 might repress PD-L1 expression and PD-1 checkpoint pathway in cancer. In this study, we revealed that CBX7 downregulated the expression of POU2F2 that indirectly repressed the PD-L1 in BC cells. Depletion of CBX7 resulted in resistance to PD-1 blockade in bladder cancer. Collectively, our results suggested that the CBX7/POU2F2/PD-L1 axis plays an important role in determining the antitumor effect of PD-1 blockade in bladder cancer.

HDAC5 modulates PD-L1 expression and cancer immunity via p65 deacetylation in pancreatic cancer.

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a dismal 5-year survival less than 10%. Most patients with PDAC exhibit poor response to single-agent immunotherapy. Multimodal therapies targeting mechanisms of resistance to immunotherapy are urgently needed. We found that the class IIa histone deacetylase (HDAC) member, HDAC5 is downregulated in multiple solid tumors and its level were associated with favorable prognosis in PDAC patients. Upregulated genes in patients harboring HDAC5 deletions were enriched in adaptive immune responses and lymphocyte-mediated immunity in The Cancer Genome Atlas (TCGA) pancreatic cancer dataset. Methods: Tissue microarray of pancreatic cancer were used to analysis the correlation between HDAC5 and PD-L1. RNA-seq, transcription factor motif analysis, drug screening and molecular biology assays were performed to identify the mechanism of HDAC5's repression on PD-L1. Allografts of pancreatic cancer in mouse were applied to test the efficiency of HDAC5 inhibition and anti-PD1 co-treatment. Results: HDAC5 regulated PD-L1 expression by directly interacting with NF-κB p65; this interaction was suppressed by p65 phosphorylation at serine-311. Additionally, HDAC5 diminished p65 acetylation at lysine-310, which is essential for the transcriptional activity of p65. Importantly, we demonstrated that HDAC5 silencing or inhibition sensitized PDAC tumors to immune checkpoint blockade (ICB) therapy in syngeneic mouse model and KPC mouse derived PDAC model. Conclusion: Our findings revealed a previously unknown role of HDAC5 in regulating the NF-κB signaling pathway and antitumor immune responses. These findings provide a strong rationale for augment the antitumor effects of ICB in immunotherapy-resistant PDAC by inhibiting HDAC5.

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and has the highest mortality rate. For metastatic RCC, systemic drug therapy is the most important method in addition to surgical tumor reduction. In recent years, tyrosine kinase inhibitors (TKIs) targeting the angiogenesis have been applied to treat ccRCC and achieved profound therapeutic effects. It has been reported that most patients receiving antiangiogenic therapy will develop resistance within 15 months. The mechanism of resistance to targeted therapy is extremely complex and has not been clarified. Ovarian tumor-associated protease domain-containing proteins (OTUDs) belonging to DUBs play a critical role in the tumorigenesis of solid tumors. However, the specific role of OTUDs in ccRCC is still elusive. Here, we investigated the clinicopathological role of OTUD family members in ccRCC. We demonstrated that OTUD1 was downregulated in renal cancer and involved in the poor prognosis of renal cancer. Then, we showed that OTUD1 inhibits cancer cell growth. Moreover, analysis of OTUD1 RNA-seq data indicated that OTUD1 inhibition triggers the AKT and NF-kappa B pathways in renal cancer cells. Furthermore, OTUD1 interacts with PTEN and regulates its stability. Subsequently, we revealed that downregulation of OTUD1 contributes to the sensitivity of renal cancer cells to TKIs, and this effect was blocked by TNF/NF-kappa B inhibitors and AKT inhibitors. Thus, we identified that the OTUD1-PTEN axis suppresses tumor growth and regulates the resistance of renal cancer to TKIs.

Smoking-associated upregulation of CBX3 suppresses ARHGAP24 expression to activate Rac1 signaling and promote tumor progression in lung adenocarcinoma.

Although tobacco smoking is a risk factor for lung adenocarcinoma (LUAD), the mechanisms by which tobacco smoking induces LUAD development remain elusive. Histone methylation levels in human bronchial epithelial cells have been reported to increase after exposure to cigarettes. In this study, we explored the mechanisms regulating histone methylation in LUAD in response to smoking. We found that the histone H3K9 methylation reader CBX3 was upregulated in current smokers with LUAD, and that CBX3 overexpression promoted LUAD progression. Functional enrichment analyses revealed that CBX3 regulated the activation of Rho GTPases in LUAD. We also found that by forming a complex with TRIM28, TRIM24, and RBBP4, CBX3 repressed the expression of ARHGAP24 and increased the amount of active Rac1 in LUAD cells. Collectively, these results suggest that smoking associated upregulation of CBX3 promotes LUAD progression by activating the ARHGAP24/Rac1 pathway. Hence, the CBX3/ARHGAP24/Rac1 axis may represent a promising therapeutic target in smoking-induced LUAD.

The clinical efficacy and safety of acupuncture intervention on cancer-related insomnia: A systematic review and meta-analysis.

Objective: To evaluate the efficacy and safety of acupuncture in treating symptoms for Cancer-related Insomnia(CRI) patients. Methods: Seven databases were searched from the time of database establishment to 31 March 2022. Randomized Controlled Trials (RCTs) on acupuncture intervention for CRI were collected. Literature screening and data extraction were performed independently by two researchers. Meta-analysis was performed using RevMan 5.4 software. Results: A total of 13 articles with 1,109 participants were included. Five hundred and seventeen in the treatment group and 592 in the control group. Ten of the RCTs used the PSQI rating scale and four randomized controlled trials used the ISI rating scale, and the PSQI and ISI were analyzed together as continuous data. The results of the meta-analysis were: MD = -1.83, 95%CI = [-2.71, -0.94], P < 0.0001, indicating a significant improvement in PSQI scores in patients with CRI by acupuncture intervention; MD = 0.79, 95%CI = [-0.46, 2.03], P = 0.22. Acupuncture was not statistically significant on ISI scores for patients with CRI compared to controls, which does not yet indicate that acupuncture is effective for symptoms in patients with CRI. The results of the meta-analysis of the other 4 items using sleep disorder logs as efficacy analysis data were as follow, relative risk RR = 0.47, 95%CI = [0.33, 0.66], P < 0.0001. The difference was statistically significant, indicating that acupuncture can improve the symptoms of CRI patients compared to control group. Conclusion: Acupuncture can improve the symptoms of patients with CRI to some extent, but due to the relatively small number and low quality of the included literature in this study, more high-quality clinical trials are needed as supplement the evidences in future. Systematic review registration: https://www.crd.york.ac.uk/prospero/.

The FOXM1/RNF26/p57 axis regulates the cell cycle to promote the aggressiveness of bladder cancer.

Bladder cancer is one of the most lethal cancers in the world. Despite the continuous development of medical technologies and therapeutic strategies, the overall survival rate of bladder cancer has not changed significantly. Targeted therapy is a new promising method for bladder cancer treatment. Thus, an in-depth study of the molecular mechanism of the occurrence and development of bladder cancer is urgently needed to identify novel therapeutic candidates for bladder cancer. Here, bioinformatics analysis demonstrated that RNF26 was one of the risk factors for bladder cancer. Then, we showed that RNF26 is abnormally upregulated in bladder cancer cells and tissues and that higher RNF26 expression is an unfavorable prognostic factor for bladder cancer. Moreover, we found that RNF26 promotes bladder cancer progression. In addition, we showed that RNF26 expression is promoted by FOXM1 at the transcriptional level through MuvB complex. The upregulated RNF26 in turn degrades p57 (CDKN1C) to regulate the cell cycle process. Collectively, we uncovered a novel FOXM1/RNF26/p57 axis that modulates the cell cycle process and enhances the progression of bladder cancer. Thus, the FOXM1/RNF26/p57 signaling axis could be a candidate target for the treatment of bladder cancer.

UBE3A activates the NOTCH pathway and promotes esophageal cancer progression by degradation of ZNF185.

Background: Esophageal cancer is the sixth-most common fatal malignant tumor worldwide. Little is known regarding the genetic drivers that influence targeted therapy outcomes in patients with esophageal cancer. Exploring the pathogenesis of this lethal tumor could provide clues for developing appropriate therapeutic drugs. Ubiquitin-protein ligase E3A (UBE3A) reportedly promotes or suppresses various types of malignant tumors. However, the cancer-related role of UBE3A in esophageal cancer remains unclear. Methods: The relationship of UBE3A with the clinicopathological features of pancreatic tumors was bioinformatically investigated in the TCGA dataset. The protein levels of UBE3A and ZNF185 were assessed by Western blot and immunohistochemistry. The role of UBE3A and ZNF185 in esophageal cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between UBE3A and ZNF185 was investigated by co-immunoprecipitation. The relationship between UBE3A, ZNF185, and NOTCH signaling pathway was explored by Western blot and quantitative real-time PCR. Results: We found that UBE3A was upregulated in patients with esophageal cancer and enhanced the cellular progression of esophageal cancer. Moreover, we found that UBE3A degraded ZNF185 in esophageal cancer. Additionally, ZNF185 suppressed the progression of esophageal cancer by inactivating the NOTCH pathway. Conclusions: These data demonstrated that aberrant expression of UBE3A led to enhanced progression of esophageal cancer through the ZNF185/NOTCH signaling axis. Therefore, UBE3A might be an ideal therapeutic candidate for esophageal cancer.

RRM2 Regulates Sensitivity to Sunitinib and PD-1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway.

Renal cell carcinoma (RCC) is a malignant tumor of the kidneys. Approximately 70% of RCC cases are clear cell renal cell carcinoma with von Hippel-Lindau (VHL) gene mutation and activation of the vascular endothelial growth factor (VEGF) pathway. Tyrosine kinase inhibitors (TKIs) targeting VEGF have emerged as promising agents for RCC treatment. Apart from primary resistance, acquired resistance to TKIs after initial tumor regression is common in RCC. Recently, immune checkpoint inhibition, including PD-1/PD-L1 blockade, alone or in combination with TKIs has improved the overall survival of patients with RCC. Ribonucleotide reductase subunit M2 (RRM2) has been reported in many types of cancer and has been implicated in tumor progression. However, the role of RRM2 in TKIs resistance in RCC remains unclear. In this study, the authors have demonstrated that RRM2 is upregulated in sunitinib-resistant RCC cells and patient tissues. They also find that RRM2 stabilizes ANXA1 and activates the AKT pathway independent of its ribonucleotide reductase activity, promoting sunitinib resistance in RCC. Moreover, RRM2 regulated antitumor immune responses, and knockdown of RRM2 enhance the anti-tumor efficiency of PD-1 blockade in renal cancer. Collectively, these results suggest that aberrantly expressed RRM2 may be a promising therapeutic target for RCC.