Ubiquitin-specific protease 22-induced autophagy is correlated with poor prognosis of pancreatic cancer

Abstract

Abstract. Ubiquitin-specific protease 22 (USP22) is a component of the transcription regulatory histone acetylation complex SAGA, which broadly regulates gene transcription and correlates with cancer progression, metastasis and prognosis. Autophagy is a cell pathway with dual functions that promotes cell survival or death. However, it is not known whether USP22 can regulate autophagy in pancreatic cancer. In the present study, we first identified that USP22 was overexpressed in a large number of pancreatic cancer patient samples, concomitant with the increased expression of LC3, a marker of autophagy. Statistical analysis revealed that the increase in USP22 and autophagy was positively correlated with poor prognosis of pancreatic cancer patients. Further investigation using a human pancreatic cancer cell (Panc-1) identified that the overexpression of USP22 increased the processing of LC3 into the active form LC3-II and the number of autophagosomes, thus leading to enhanced autophagy. Activation of ERK1/2 kinase rather than AKT1 by USP22 was found to be one of the mechanisms promoting LC3 processing. USP22-induced autophagy was also found to enhance cell proliferation and resistance to starvation and chemotherapeutic drugs in Panc-1 cells, therefore expressing an overall effect that promotes cell survival. Collectively, the present study demonstrated a new function of USP22 that induces autophagy, thus leading to the poor prognosis of pancreatic cancer.

ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth

“…Several reports indicate that USP22 overexpression is linked to unfavorable outcomes in multiple types of cancers (He et al, 2015; Liang et al, 2014; Ning et al, 2012; Zhang et al, 2011). However, the mechanisms underlying USP22 overexpression in different malignancies and molecular links between histone deubiquitination and aggressive tumor growth are still not clear.…”

Prognostic and clinicopathological significance of ubiquitin-specific protease 22 overexpression in cancers: evidence from a meta-analysis

“…All studies were performed exclusively in patients from China. Seven of the studies were of patients with digestive system cancers (colorectal cancer, hepatocellular cancer, esophageal cancer, gastric cancer, and pancreatic cancer), 16 , 18 , 23 , 28 – 31 two of the studies were of patients with salivary carcinoma, 20 , 22 and seven of the studies were of patients with other cancer types (oral squamous cell carcinoma, lung cancer, glioma cancer, breast cancer, epithelial ovarian cancer, and papillary thyroid carcinoma). 17 , 19 , 21 , 32 – 35 IHC was the main method used to detect USP22 expression in these studies.…”

USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating γH2AX-Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis

“…Recent studies reported that overexpression of USP22 may be involved in the drug resistance of cancer through a variety of mechanisms. Our published research has demonstrated that USP22 was related to the chemotherapy resistance to gemcitabine in pancreatic cancer (Liang et al, 2014). A recent study suggested that cisplatin can suppress the expression of USP22 through p38/MAPK pathway in HeLa cells (Ding et al, 2014).…”