UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1

Abstract

Background Ubiquitin-like protein 4A (UBL4A) plays a significant role in protein metabolism and the maintenance of cellular homeostasis. In cancer, UBL4A represses tumorigenesis and is involved in various signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) is still a major cause of cancer-related death and the underlying molecular mechanism of UBL4A and PDAC remains unknown. Methods First, the prognostic role of UBL4A and its expression in human PDAC patients and in pancreatic cancer cell lines were detected by survival analysis and qRT-PCR, western blotting, and immunohistochemistry. Next, the effects of UBL4A on proliferation and metastasis in pancreatic cancer were evaluated by functional assays in vitro and in vivo. In addition, chloroquine was introduced to determine the role of autophagy in UBL4A-related tumor proliferation and metastasis. Ultimately, coimmunoprecipitation was used to confirm the interaction between UBL4A and lysosome associated membrane protein-1 (LAMP1), and western blotting was performed to explore the UBL4A mechanism. Results We found that UBL4A was decreased in PDAC and that high levels of UBL4A correlated with a favorable prognosis. We observed that UBL4A inhibited tumor proliferation and metastasis through suppression of autophagy, a critical intracellular catabolic process that reportedly protects cells from nutrient starvation and other stress conditions. UBL4A caused impaired autophagic degradation in vitro, a crucial process in autophagy, by disturbing the function of lysosomes and contributing to autophagosome accumulation. We found a positive correlation between UBL4A and LAMP1. Furthermore, UBL4A caused lysosomal dysfunction by directly interacting with LAMP1, and LAMP1 overexpression reversed the antitumor effects of UBL4A in pancreatic cancer. In addition, we demonstrated that UBL4A suppressed tumor growth and metastasis in a pancreatic orthotopic tumor model. Conclusions These findings suggest that UBL4A exerts an antitumor effect on autophagy-related proliferation and metastasis in PDAC by directly targeting LAMP1. Herein, we describe a novel mechanism of UBL4A that suppresses the progression of pancreatic cancer. UBL4A might be a promising target for the treatment and prognostication of PDAC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1278-9) contains supplementary material, which is available to authorized users.

The Role of Autophagy in Pancreatic Cancer—Recent Advances

“…Other evidence also suggests that metabolic changes in PDAC drive the transcriptional activation of lysosome biogenesis [46]. A recent study has identified ubiquitin-like protein 4A (UBL4A), a tumor suppressor mediating cell death in response to DNA damage [47], and a protein folding chaperone [48], to directly interact with LAMP1 [49]. The interaction between UBL4A and LAMP1 is thought to disturb lysosome function and thus impair autophagic degradation, as observed by the autolysosome accumulation and lysosomal disfunction in cells with higher UBL4A levels [49].…”

“…A recent study has identified ubiquitin-like protein 4A (UBL4A), a tumor suppressor mediating cell death in response to DNA damage [47], and a protein folding chaperone [48], to directly interact with LAMP1 [49]. The interaction between UBL4A and LAMP1 is thought to disturb lysosome function and thus impair autophagic degradation, as observed by the autolysosome accumulation and lysosomal disfunction in cells with higher UBL4A levels [49]. Furthermore, the analysis of UBL4A expression in 69 PDAC patients revealed that patients with higher levels of UBL4A mRNA in PDAC tissue have improved survival rates [49], perhaps due to also having lower autophagy levels.…”

USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer

“…The other DUBs identified in our screen had a much lower Spearman correlation than that of USP1 and TAZ (UCK2: rho = 0.18; UBL4A: rho = −0.13; UCHL1: rho = 0.29). Since USP1 is known to act in an oncogenic manner while UCHL1 and UBL4A are shown to have tumor-suppressive functions, we focused our studies on how USP1 alters TAZ [ 27 , 28 , 29 ]. To understand the expression of USP1 and TAZ at the protein level, we analyzed a panel of breast cancer cell lines.…”

Oncolytic Adenovirus Expressing ST13 Increases Antitumor Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Against Pancreatic Ductal Adenocarcinoma

“…PDAC is a common malignant tumor worldwide. [31][32][33][34] Although different approaches are offered for the treatment of PDAC, all deliver unsatisfactory results, characterized by high levels of tumor metastasis and poor prognosis. Thus, there is an urgent need to develop novel therapeutic strategies that have high efficacy with low adverse effects for targeting malignant tumors, especially metastatic tumors.…”