DUSP22, belonging to members of the dual-specificity phosphatases (DUSPs) family, can control the activity of various protein kinases and transcription factors through the dephosphorylation process. Many DUSP22-targeted proteins are involved in signaling pathways that are crucial for tumorigenesis, and inflammation. Genetic alteration of DUSP22 or DUSP22 downregulation was observed in some cancers. However, little is known about the roles of DUSP22 during tumor suppression. Here, utilizing TGCA databases, our analysis showed low DUSP22 expression is associated with shorter disease-free survival of lung and prostate cancer patients. The IL-6/STAT3 and EGFR/ERK1/2 axes are generally recognized as an important oncogenic and mitogenic pathway in prostate cancer. We found that DUSP22 expression markedly reduced p-STAT3 (Tyr705), and p-EGFR (Tyr1068)/p-ERK1/2 expression levels after IL-6 and EGF stimulation, respectively, in prostate cancer cells. Similarly, DUSP22 can inhibit the EGFR/ERK1/2 axis in lung cancer cells that harbor EGFR exon 19 deletion mutation, supporting a repressive role for DUSP22 in regulating growth receptor signaling pathways. In addition, we found the exogenous expression of DUSP22 significantly reduced the cell growth of prostate and lung cancer cells. More importantly, DUSP22 can serve as a negative regulator of androgen receptor in prostate cancer cells through reducing EGF-induced AR phosphorylation and inhibiting DHT-mediated nuclear AR translocation. Taken together, our current data indicate that loss of DUSP22 function or DUSP22 downregulation may accelerate lung and prostate tumorigenesis through EGFR-dependent pathways. Importantly, it has been reported that increased PD-L1 expression by EGFR activation mediates the immune escape in EGFR-driven lung cancer (NSCLC). We found that the inhibition of the EGFR signaling by DUSP22 can reduce PD-L1 expression in both lung and prostate cancer cells, suggesting that loss of DUSP22 function in cancer cells may not only enhance cell growth, but also potentially repress antitumor immunity through upregulation of PD-L1. Our findings implicate that anti-PD1/PD-L1 therapy could be a potential option if lung or prostate cancer patients are found with low DUSP22 expression. Currently, we are using multiple approaches to elucidate molecular mechanisms of DUSP22 ablation for accelerating lung and prostate tumorigenesis in vivo.
Citation Format: Wen-Jye Lin, Cheng-Wei Chang, Hsiu-Ping Lin, Hui-Min Ho. Molecular mechanisms of dual-specificity phosphatase 22 (DUSP22) in suppression of tumorigenesis: The potential involvement of the EGFR/PD-L1 axis [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B172.