Deubiquitinase ubiquitin‐specific peptidase 10 maintains cysteine rich angiogenic inducer 61 expression via Yes1 associated transcriptional regulator to augment immune escape and metastasis of pancreatic adenocarcinoma

Abstract

Pancreatic adenocarcinoma (PAAD) remains an extremely fatal malignancy with a high mortality rate worldwide. This study focuses on the roles of ubiquitin‐specific peptidase 10 (USP10) and cysteine rich angiogenic inducer 61 (Cyr61) in macrophage polarization, immune escape, and metastasis of PAAD. USP10 showed a positive correlation with Yes1 associated transcriptional regulator (YAP1), which, according to the TCGA‐PAAD database, is highly expressed in PAAD and indicates poor patient prognosis. USP10 knockdown increased ubiquitination and degradation of YAP1, which further decreased the programmed cell death ligand 1 (PD‐L1) and Galectin‐9 expression, suppressed immune escape, and reduced the proliferation and metastasis of PAAD cells in vitro and in vivo. Cyr61, a downstream factor of YAP1, was overexpressed in PAAD cells after USP10 silencing for rescue experiments. Overexpression of Cyr61 restored the PD‐L1 and Galectin‐9 expression in cells and triggered M2 polarization of macrophages, which enhanced the immune escape and maintained the proliferation and metastasis ability of PAAD cells. In conclusion, this work demonstrates that USP10 inhibits YAP1 ubiquitination and degradation to promote Cyr61 expression, which induces immune escape and promotes growth and metastasis of PAAD.

USPs in Pancreatic Ductal Adenocarcinoma: A Comprehensive Bioinformatic Analysis of Expression, Prognostic Significance, and Immune Infiltration

“…Ultimately, we explored the potential functions and pathways of six-USPs using positively coexpressed genes by GO and KEGG enrichment analyses. Although the roles of some members of six-USPs in PDAC initiation and progression have been previously reported, these studies remained relatively superficial and comprehensive, and in-depth analysis of the potential mechanisms of six-USPs in PDAC has yet to be performed [24][25][26][27]. Our study comprehensively analyzed the expression status, clinicopathological characteristic relationship, prognostic significance, immune infiltration and functions, and pathway enrichment analysis of six USP family members (USP10, USP14, USP18, USP32, USP33, and USP39) in PDAC for the first time.…”

“…Besides, several articles have indicated the roles of USP10 in pancreatic cancer. The study of Liu et al showed that USP10 could stabilize Yes1-associated transcriptional regulator expression which, whereafter enhanced cysteine rich angiogenic inducer 61 expression to promote immune escape and maintain cell proliferation and metastasis ability via the upregulation of PD-L1 and galectin-9 [ 24 ]. Recently, a bioinformatic study comprehensively analyzed the prognostic value and immune infiltration of USP10 in pan-cancer, especially in PDAC and hepatocellular carcinoma [ 32 ].…”

Ubiquitin-specific peptidase 10, a deubiquitinating enzyme: Assessing its role in tumor prognosis and immune response

“…The role of USP10 in pancreatic cancer remains controversial. For example, Liu et al reported that USP10 promoted Cysteine-Rich 61 (Cyr61) expression by inhibiting YAP1 ubiquitination and degradation, thereby favoring immune escape and promoting the proliferation and metastasis of pancreatic cancer ( 19 ). However, another study suggested that miR-191 promotes pancreatic cancer cell proliferation by inhibiting USP10 expression ( 76 ).…”

“…Moreover, it may affect the development of various cancers, including lung cancer ( 16 ), liver cancer ( 17 ), and acute myeloid leukemia (AML) ( 18 ). Interestingly, it also modulates immune-related signaling pathways via deubiquitination of immune-related genes, such as yes-associated protein 1 (YAP1) ( 19 ). The relationship between the abnormal expression of USP10 in various tumors and its regulation of immune pathways prompted us to explore the role of USP10 in tumor development and immunity.…”

Ubiquitin‐specific peptidase 10 attenuates the ferroptosis to promote thyroid cancer malignancy by facilitating GPX4 via elevating SIRT6

“…9 Moreover, USP10 has been implied to promote the progression of pancreatic adenocarcinoma by augmenting the metastasis, proliferation and immune escape of pancreatic adenocarcinoma cells. 10 However, the loss of USP10 has been demonstrated to intensify the tumorigenesis of lung cancer. 11 Thus, the function of USP10 in cancer varies by the types of cancer.…”