The USP22 promotes the growth of cancer cells through the DYRK1A in pancreatic ductal adenocarcinoma

Highlights

• USP22 expression is increased in PDAC tissues and cells.

• USP22 promotes the growth of PDAC cells.

• USP22 promotes the expression of DYRK1A.

• DYRK1A contributes to the function of USP22 in the regulation of cell growth.

Abstract

As a member of the ubiquitin-specific protease (USP) family, USP22 could remove ubiquitin moieties from its target proteins to control the function of the target proteins. Accumulating studies show that USP22 essentially participates in diverse types of cancer as an oncogene-like protein. However, the roles of USP22 in human pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanism are unknown. Here we report that USP22 promotes the growth of PDAC cells by promoting the expression of dual-specificity tyrosine regulated kinase 1A (DYRK1A). Our results showed that the expression levels of USP22 were up-regulated in human PDAC tissues and cell lines (BxPC-3, AsPC-1, MIA-PaCa-2, PANC-1, and CAPAN-1). Lentivirus-mediated knockdown of USP22 repressed the rate of proliferation and capacity of colony formation of BxPC3 and CAPAN1 cancer cells and USP22 overexpression promoted the proliferation and capacity of the colony formation of BxPC3 and CAPAN1 cancer cells. The further mechanism study showed that USP22 elevated the expression of the mRNA and protein levels of DYRK1A in PDAC cancer cells. Inhibition of DYRK1A with EHT-5732 or lentivirus-mediated knockdown of DYRK1A blocked the function of USP22 overexpression in the regulation of the proliferation and colony formation of PDAC cells. Taken together, our findings demonstrated that USP22 overexpression in PDAC promoted the growth of the cancer cells partially through upregulating the expression of DYRK1A.

Introduction

Protein ubiquitination is a revisable modification that controlling the stability of the proteins. Ubiquitin-specific proteases (USPs) family members can remove ubiquitin moieties from their target proteins. By inhibiting the ubiquitin-dependent degradation progress, USPs could stabilize their substrate proteins. As a member of the USP family, USP22 functions as one of the core components of the mammalian transcriptional coactivating complex SPT‐ADA‐GCN5 acetyltransferase. USP22 can deubiquitinate SIRT1 and antagonize the transcriptional activity of p53 to suppress cell apoptosis, which is conserved in the mouse embryonic development progress (Lin et al., 2012). Phosphorylation of histone demethylase LSD1 (KDM1A) induces its binding with USP22, which leads to the deubiquitylation and stabilization of KDM1A (Zhou et al., 2016). Additionally, USP22 also promotes the switch recombination of antibody class through activating the non-homologous end-joining (Li et al., 2018). Furthermore, USP22 is a positive regulator of the nuclear factor of activated T cells c2 (NFATc2) on promoting interleukin 2 expression in T cells (Gao et al., 2014). Interestingly, USP22 also facilitates the expression level of the regulator of calcineurin 1 (RCAN1), consequently influencing various RCAN1‐linked cellular functions, including the inflammatory response (Hong et al., 2015).

The roles of USP22 in human cancers have been identified. In patients with invasive breast cancer, the elevated expression of USP22 is associated with poor prognosis (Zhang et al., 2011). In hepatocellular carcinoma, a high level of USP22 expression predicts poor prognosis (Tang et al., 2015). USP22 also promotes the proliferation and metastasis in anaplastic thyroid cancer cells (Zhao et al., 2016). In human esophageal squamous cell carcinoma, the nuclear USP22 is remarkedly associated with the developmental progression and unfavorable clinical outcomes (Li et al., 2012). In salivary duct carcinoma, Increased expression of USP22 is associated with disease progression and patient prognosis of salivary duct carcinoma (Piao et al., 2013). USP22 serves as a critical participator of tumor initiation and progression, implicating that USP22 could be a promising target for treating advanced cancer (Schrecengost et al., 2014).

The DYRK1A protein (dual-specificity tyrosine-phosphorylation-regulated kinase 1A) is one of the members of the CMGC group of kinases, which is an evolutionarily conserved family of protein kinases. DYRK1A participates in the regulation of the enhancer by interacting with the histone acetylase component p300 and modulating its activity (Li et al., 2018). In endothelial cells, the DYRK1A kinase positively regulates angiogenesis (Rozen et al., 2018). The DYRK1A is essentially involved in neuron development, degeneration, and diseases (Abbassi et al., 2015). In human pluripotent stem cells, DYRK1A inhibition disrupts neural lineage specification (Bellmaine et al., 2017). The roles of DYRK1A in tumor biology was also identified in recent years. In head and neck squamous cell carcinoma, DYRK1A functions as a potential therapeutic target. A recent report showed that DYRK1A regulates c-MET to drive tumor growth in pancreatic ductal adenocarcinoma (Luna et al., 2018).

In this study, we aimed to investigate the function of USP22 in human pancreatic ductal adenocarcinoma and the potential mechanism. Our findings revealed that USP22 expression was increased in human PDAC tissues and cell lines. USP22 promoted the rate of proliferation and capacity of colony formation of PDAC cells by increasing the expression of DRYK1A. Inhibition of the activity of DRYK1A and DRYK1A knockdown repressed the function of USP22 in the regulation of proliferation and colony formation of PDAC cells.