The deubiquitinating enzyme PSMD14 facilitates tumor growth and chemoresistance through stabilizing the ALK2 receptor in the initiation of BMP6 signaling pathway

Abstract

Background: Although bone morphogenetic protein 6 (BMP6) signaling pathway has been implicated in many types of cancer, its role of tumorigenesis seems to be controversial and its ubiquitin-modifying mechanisms have not been fully addressed. Our study was designed to investigate how BMP6 signaling pathway is regulated by ubiquitin-modifying systems and to address molecular and clinical significance in colorectal cancers. Methods: Human deubiquitnase (DUB) siRNA library was used to screen the specific DUB, named PSMD14, involved in BMP6 signaling pathway. Immunoblot, immunoprecipitation and ubiquitination assays were used to analyze targets of the PSMD14. A role of PSMD14-mediated BMP6 signaling pathway for malignant cancer progression was investigated using in vitro and in vivo model of colorectal cancers as well as clinical samples of colorectal cancer patients. Findings: The deubiquitinase PSMD14 acts as a positive regulator for the initiation of the BMP6 signaling pathway through deubiquitinating K48-linked ALK2 type I receptor ubiquitination mediated by Smurf1 E3 ligase, resulting in increased stability of the ALK2. This role of PSMD14 is independent of its intrinsic role in the 26S proteasome system. Furthermore, either PSMD14 or ALK2 depletion significantly decreases tumorigenesis of HCT116 colorectal cancer cells in a xenograft model as well as cancer stemness/chemoresistance, and expression of the PSMD14 and ALK2 gene are correlated with malignant progression and the survival of colorectal cancer patients. Interpretation: These findings suggest that the PSMD14-ALK2 axis plays an essential role in initiation of the BMP6 signaling pathway and contributes to tumorigenesis and chemoresistance of colorectal cancers.

The PSMD14 inhibitor Thiolutin as a novel therapeutic approach for esophageal squamous cell carcinoma through facilitating SNAIL degradation

“…PSMD14 could remove the ubiquitin chain from targeted proteins at the entrance of 19S proteasome, facilitating proteins to translocate into the 20S proteasome subunit for further degradation 36 , 37 . On the contrary, previous studies revealed that as a DUB, PSMD14 could also suppress the degradation of specific proteins, such as E2F1 14 , GRB2 38 and ALK2 receptor 39 . Consequently, PSMD14 is speculated to possess a 'proofreading' function, like a “controller” of recycling station, to determine the fate of substrates.…”

Immune prognostic implications of PSMD14 and its associated genes signatures in hepatocellular carcinoma

“…The deubiquitinase (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14, RPN11 or POH1), belongs to the JAMM domain metalloprotease family of DUBs and is an important part of 19S regulatory cap in 26S proteasome [5]. PSMD14 has been confirmed to play vital roles in gene ontology and related pathway, including protein stability [6], tumour formation [7], transcriptional regulation [8], double-strand DNA break repair [9], senescence [10], apoptosis and resistance [11], growth and metastasis [5], BMP6 signaling [6], TGF-β signaling [8]. Recently, PSMD14 has been overexpressed in many human cancers, such as HCC, colorectal cancer, multiple myeloma, esophageal squamous cell carcinoma and breast cancer, which it This is related to the poor prognosis of the patients [5,6,[11][12][13].…”

“…PSMD14 acts as an oncogene that promotes tumor progression by deubiquitinating of different protein substrates. For example, Deubiquitinase PSMD14 acts as a positive regulator for the initiation of the BMP6 signalling pathway, resulting in increased stability of the ALK2, either PSMD14 or ALK2 depletion significantly decreases colorectal cancer growth and chemoresistance [6]. Similarly, PSMD14 inhibits degradation of GRB2 by deubiquitinating this oncoprotein and stabilizing GRB2, which it enhances hepatocellular carcinoma growth and metastasis [5].…”

Immune Prognostic Implications of PSMD14 and Its Associated Genes Signatures in Hepatocellular Carcinoma

“…The deubiquitinase (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14, RPN11 or POH1), belongs to the JAMM domain metalloprotease family of DUBs and is an important part of 19S regulatory cap in 26S proteasome (6). PSMD14 has been con rmed to play vital roles in gene ontology and related pathway, including protein stability (7), tumour formation (8), transcriptional regulation (9), double-strand DNA break repair (10), senescence (11), apoptosis and resistance (12), growth and metastasis (6), BMP6 signaling (7), TGF-β signaling (9). Recently, it has been found that PSMD14 is overexpressed in many human cancers, such as HCC, colorectal cancer, multiple myeloma, esophageal squamous cell carcinoma and breast cancer, which are related to the poor prognosis of the patients (6,7,(12)(13)(14).…”

“…For example, Deubiquitinase PSMD14 positively regulates the initiation of the BMP6 signalling pathway, resulting in increased stability of the ALK2. Either PSMD14 or ALK2 depletion signi cantly decreases colorectal cancer growth and chemoresistance (7). GRB2 is an oncoprotein that enhances hepatocellular carcinoma growth and metastasis.…”