| Colorectal cancer is the third most common cancer worldwide,with the second leading cause of cancer death.According to the 2020 China Colorectal Cancer Screening,Early Diagnosis and Early Treatment Guidelines,the prevalence of colorectal cancer in China is on the rise,with increasing incidence trend in the younger population.Inflammatory bowel disease,diabetes,obesity,unhealthy dietary patterns and lifestyle increase the risk of developing colorectal cancer.Tumor immunotherapy is an anti-cancer strategy emerging in recent years.Through activation of host immune response against malignant disease,tumor immunotherapy has made great progress in multiple types of cancers.However,only a small subset of patients with colorectal tumors achieve long term benefit with immune checkpoint blockade.It is thus important to explore a new way to weaken immunosuppression and augment immunogenicity in colorectal cancer.In human,inorganic ions play an important role in maintaining intracellular and extracellular osmotic pressure and acid-base balance.Additionally,many ions are involved in the regulation of host antitumor immunity.For instance,high level of extracellular potassium constrains T cell effector function and promotes tumor immune escape.Calcium and magnesium can enhance the macrophage phagocytosis of tumor cells.Manganese enhances the presentation of neoantigens by antigen-presenting cells,which in turn increases tumorinfiltrating cytotoxic T cells and augments tumor clearance.As an essential trace element,iron is a cofactor for many metabolic enzymes and is required for cell growth and proliferation.However,the status and regulatory role of iron metabolism within tumor development remains elusive.In this study,we identified the deubiquitinase OTUD1 enhanced antitumor immune responses and alleviated colorectal cancer development through promoting iron transportation.Firstly,through a series of assays including bioinformatics analysis,mass spectrometry,in vivo and in vitro ubiquitination assay,we revealed that OTUD1 targeted iron-responsive elementbinding protein 2(IREB2)and stabilized IREB2 by effectively removing K48-linked polyubiquitin chain of IREB2.Increased IREB2 promoted downstream transferrin receptor(TFRC)translation,eventually resulting in iron influx.Subsequently,we used Otud1 knockout mice and induced mice iron-deficiency anemia.By blood routine testing,Otud1 knockout mice were more susceptible to iron-deficiency diet induced anemia,which further confirmed the key role of OTUD1 in maintain of iron homeostasis.To elucidate the biological function of OTUD1 in tumor initiation and development,we examined colon cancer tissues and their matched adjacent normal tissues and found that OTUD1-IREB2-TFRC signaling was significantly silenced in tumor tissues.In addition,we noticed that low expression of OTUD1 was highly correlated with poor prognosis of colorectal cancer patients through analysis of clinical information.Moreover,we performed subcutaneous xenograft model and azoxymethane(AOM)/dextran sulfate sodium(DSS)-induced colitis-associated colorectal cancer(CAC)model and defined that OTUD1 significantly limited tumor size and prolonged the survival time of tumor-bearing mice,while loss of OTUD1 promoted tumor growth in vivo,although in vitro cell proliferation assay and tumor transplantation in nude mice showed that OTUD1 did not affect tumor intrinsic growth.Mechanically,activation of OTUD1-IREB2-TFRC signaling promoted iron uptake and thus increased intracellular reactive oxygen species(ROS),thereby enhancing ferroptosis of tumor cells.By tumor vaccine models,we also demonstrated that OTUD1-mediated ferroptosis is a type of immunogenic cell death(ICD),which promoted immune cell recruitment and aggravated host antitumor response.Our study shed light on a new mechanism of deubiquitinase OTUD1-mediated iron transport and revealed the importance of OTUD1-IREB2-TFRC signaling in host antitumor immunity.Our findings may pave the way to the development of potential therapeutic target and prognostic diagnostic marker in colorectal cancer. |
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