SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

The ubiquitin-like protein FAT10 in hepatocellular carcinoma cells limits the efficacy of anti-VEGF therapy by accelerating VEGF-independent angiogenesis.

INTRODUCTION: The efficacy of anti-vascular endothelial growth factor (VEGF) therapy is limited. However, the key factors involved in limiting the efficacy of anti-VEGF therapy and the underlying mechanisms remain unclear. OBJECTIVES: To investigate the effects and mechanisms of human leukocyte antigen F locus-adjacent transcript 10 (FAT10), a ubiquitin-like protein, in limiting the efficacy of anti-VEGF therapy in hepatocellular carcinoma (HCC) cells. METHODS: FAT10 was knocked out in HCC cells using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 technology. Bevacizumab (BV), an anti-VEGF monoclonal antibody, was used to evaluate the efficacy of anti-VEGF therapy in vivo. Mechanisms of FAT10 action were assessed by RNA sequencing, glutathione S-transferase pulldown assays and in vivo ubiquitination assays. RESULTS: FAT10 accelerated VEGF-independent angiogenesis in HCC cells which limited BV efficacy and BV-aggravated hypoxia and inflammation promoted FAT10 expression. FAT10 overexpression increased levels of proteins involved in several signaling pathways in HCC cells, resulting in upregulation of VEGF and multiple non-VEGF proangiogenic factors. Upregulation of multiple FAT10-mediated non-VEGF signals compensated for the inhibition of VEGF signaling by BV, enhancing VEGF-independent angiogenesis and promoting HCC growth. CONCLUSIONS: Our preclinical findings identify FAT10 in HCC cells as a key factor limiting the efficacy of anti-VEGF therapy and elucidate its underlying mechanisms. This study provides new mechanistic insights into the development of antiangiogenic therapies.

Ubiquitin-like protein FAT10 promotes bladder cancer progression by stabilizing survivin.

Human HLA-F adjacent transcript 10 (FAT10) is a member of the ubiquitin-like-modifier family of proteins, which have been implicated in cancer development. In addition, the Survivin protein promotes proliferation in bladder cancer (BC). In this study, we explored the link between FAT10 and Survivin. FAT10 expression was dramatically up-regulated in BC tissue samples, and Kaplan-Meier survival analysis revealed that BC patients with high FAT10 expression had shorter overall survival than those with low FAT10 expression. Moreover, RNAi-mediated FAT10 knockdown decreased Survivin protein levels and inhibited BC proliferation both in vitro and in vivo. FAT10 directly bound to and stabilized Survivin protein, thereby promoting cancer cell proliferation by inhibiting ubiquitin-mediated degradation. These results reveal a novel mechanism by which FAT10 promotes tumor proliferation by directly stabilizing Survivin protein in BC.