Systematic analysis reveals a functional role for STAMBPL1 in the epithelial–mesenchymal transition process across multiple carcinomas

Abstract

Background Deubiquitinating enzymes (DUBs) are linked to cancer progression and dissemination, yet less is known about their regulation and impact on epithelial–mesenchymal transition (EMT). Methods An integrative translational approach combining systematic computational analyses of The Cancer Genome Atlas cancer cohorts with CRISPR genetics, biochemistry and immunohistochemistry methodologies to identify and assess the role of human DUBs in EMT. Results We identify a previously undiscovered biological function of STAM-binding protein like 1 (STAMBPL1) deubiquitinase in the EMT process in lung and breast carcinomas. We show that STAMBPL1 expression can be regulated by mutant p53 and that its catalytic activity is required to affect the transcription factor SNAI1. Accordingly, genetic depletion and CRISPR-mediated gene knockout of STAMBPL1 leads to marked recovery of epithelial markers, SNAI1 destabilisation and impaired migratory capacity of cancer cells. Reversely, STAMBPL1 expression reprogrammes cells towards a mesenchymal phenotype. A significant STAMBPL1-SNAI1 co-signature was observed across multiple tumour types. Importantly, STAMBPL1 is highly expressed in metastatic tissues compared to matched primary tumour of the same lung cancer patient and its expression predicts poor prognosis. Conclusions Our study provides a novel concept of oncogenic regulation of a DUB and presents a new role and predictive value of STAMBPL1 in the EMT process across multiple carcinomas.

Identification of ubiquitination-related gene classification and a novel ubiquitination-related gene signature for patients with triple-negative breast cancer

“…The study by Liu et al (2022) found that STAMBPL1 interacts with MKP-1 and stabilizes MKP-1 via deubiquitination, further promoting breast cancer cell resistance to cisplatin. Moreover, STAMBPL1 could regulate snail stability by deubiquitination mechanisms in breast cancer (Ambroise et al, 2020). The aforementioned studies showed that STAMBPL1 is a risk factor for breast cancer, which is contrary to our result.…”

Mutant p53 as a Regulator and Target of Autophagy

“…It is well known that the EMT pathway is under the negative regulation of wild type p53, while mutant p53 proteins display oncogenic GOF activities with robust capacity to promote EMT by controlling the TGF- β signaling and by regulating the expression of various pro-EMT-Transcription factors ( 130 , 131 ). Furthermore, considering that the metastatic potential of cancer cells increases along the EMT process, multitude of key metabolic pathways, including glycolysis, the TCA cycle, lipid and amino acid metabolism, have been attributed to contribute to EMT, tumor aggressiveness and invasiveness ( 132 , 133 ).…”

Helicobacter pylori-induced reactive oxygen species direct turnover of CSN-associated STAMBPL1 and augment apoptotic cell death

“…The deubiquitinylating enzyme STAM-binding protein like 1 (STAMBPL1), a member of the JAMM family of DUBs, comprises metalloprotease activity and cleaves K63 as well as K48 ubiquitin linkages [ 6 , 7 ]. Structurally, STAMBPL1 is closely related to associated molecule with the SH3 Domain of STAM (AMSH).…”

“…AMSH is known as an endosome-associated DUB playing a critical role in endosomal-lysosomal sorting to facilitate the recycling of cell-surface receptors by removing K63-linked polyubiquitin on the substrates [ 9 ]. On the other hand, STAMBPL1 has a function in the regulation of cell survival [ 10 , 11 ] and plays a role in the regulation of transactivator from the X-gene region (Tax)-mediated NF-κB activation [ 12 ] and epithelial-mesenchymal transition (EMT) [ 7 ]. STAMBPL1 expression is ubiquitous among a variety of human tissues [ 8 ] and shows overexpression in human cancer [ 7 ].…”

“…On the other hand, STAMBPL1 has a function in the regulation of cell survival [ 10 , 11 ] and plays a role in the regulation of transactivator from the X-gene region (Tax)-mediated NF-κB activation [ 12 ] and epithelial-mesenchymal transition (EMT) [ 7 ]. STAMBPL1 expression is ubiquitous among a variety of human tissues [ 8 ] and shows overexpression in human cancer [ 7 ]. However, its regulation in response to chemotherapeutic agents and particularly in microbial infection by H. pylori is unknown.…”