Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis.

BACKGROUND: The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive. METHODS: We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo. RESULTS: TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15. CONCLUSIONS: TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.

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.

ITGA2 overexpression inhibits DNA repair and confers sensitivity to radiotherapies in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a 5-year survival rate of less than 10%, despite the recent advances in chemoradiotherapy. The sensitivity of the PDAC patients to chemoradiotherapy varies widely, especially to radiotherapy, suggesting the need for more elucidation of the underlying mechanisms. In this study, a novel function of the nuclear ITGA2, the alpha subunit of transmembrane collagen receptor integrin alpha-2/beta-1, regulating the DNA damage response (DDR), was identified. First, analyzing The Cancer Genome Atlas (TCGA) PDAC data set indicated that the expression status of ITGA2 was negatively correlated with the genome stability parameters. The study further demonstrated that ITGA2 specially inhibited the activity of the non-homologous end joining (NHEJ) pathway and conferred the sensitivity to radiotherapy in PDAC by restraining the recruitment of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to Ku70/80 heterodimer during DDR. Considering the overexpression of ITGA2 and its associated with the poor prognosis of PDAC patients, this study suggested that the ITGA2 expression status could be used as an indicator for radiotherapy and DNA damage reagents, and the radiotherapy in combination with the overexpression of ITGA2 might be a viable treatment strategy for the PDAC patients.

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.

Prognostic Analysis of Different Metastatic Patterns in Invasive Intraductal Papillary Mucinous Neoplasm: A Surveillance, Epidemiology, and End Results Database Analysis.

Objective: To evaluate the impacts of different metastatic patterns on the prognosis of patients with invasive intraductal papillary mucinous neoplasm (IPMN). Materials and Methods: All patients who were diagnosed with invasive IPMN in the Surveillance, Epidemiology, and End Results SEER database (2010-2015) were included in this study. They were grouped according to different metastatic patterns. Kaplan-Meier analysis and log-rank test were used for the comparison of their survival rates. The hazard ratio (HR) with 95% confidence interval (CI) was analyzed using the Cox proportional-hazards model. Results: A total of 2264 cases were included in this study. The most common metastatic site was the liver. The patients with the nonorgan metastasis demonstrated the best survival outcomes, while those with multiple metastases showed the worst survival outcomes. As compared to the patients with isolated liver metastasis, those with isolated lung and other organ metastases showed better overall survival rates and tumor-specific survival rates. The patients with liver, lung, multiple, and other organ metastases or of age >60 years were the independent predictors of poor prognosis. Conclusions: The patients with isolated lung and other organ metastases demonstrated better survival outcomes as compared to those with isolated liver metastasis. The patients with nonorgan metastasis demonstrated the best survival outcomes, while those with multiple metastases showed the worst survival outcomes. Further studies are needed to determine a highly selected subset of patients, who might benefit from surgery or chemotherapy.

Metformin activates the STING/IRF3/IFN-ß pathway by inhibiting AKT phosphorylation in pancreatic cancer.

The anti-diabetes drug metformin has emerged as a promising antitumor agent in pancreatic ductal adenocarcinoma (PDAC) among other cancers by promoting the infiltration of immune cells in the tumor microenvironment (TME). However, the mechanisms underlying the antitumor effects of metformin in PDAC remain unclear. In this study, we revealed that metformin induced stimulator of interferon genes (STING) expression in pancreatic cancer cells in a dose- and time-dependent manner. Metformin also activated the STING/IRF3/IFN-ß pathway by inhibiting AKT signaling in PDAC cells. Importantly, the combination of metformin with the STING agonist 2'3'-cGAMP exerted synergistic effects in activating the STING/IRF3/IFN-ß pathway in pancreatic cancer cells. Additionally, metformin augmented the antitumor effects of 2'3'-cGAMP in mouse models by enhancing the infiltration of T cells in the TME. These findings unveiled a previously unknown mechanism contributing to the antitumor effects of metformin in PDAC, and provide a rationale for its use in combination with existing or novel immunotherapies.