Deubiquitinase OTUB2 promotes intrahepatic cholangiocarcinoma progression by stabilizing the CTNNB1-ZEB1 axis

Intrahepatic cholangiocarcinoma (iCCA), a highly lethal cancer of the liver bile ducts, has been increasing in incidence for several decades, with few effective treatments available [1]. Radical resection is the main treatment for early-stage patients, and chemotherapy with gemcitabine/cisplatin is the first-line treatment for advanced cancers [2,3]. As a result of its silent and asymptomatic nature, especially in the early stages, as well as its high aggressiveness, intra- and intertumor heterogeneity and chemoresistance, current therapies are limited in efficacy, leading to a poor prognosis [4]. Therefore, exploring the genes related to the invasion and metastasis of iCCA and clarifying their internal molecular mechanism could reveal more effective methods for the treatment of iCCA.

Proteins are the executors of gene function. Dysregulation of their expression and function is closely related to the occurrence and development of malignant tumors. Studies have shown that posttranslational ubiquitination is one of the key mechanisms that regulates protein expression and activity. Enzymes related to ubiquitination modification include E1 activating enzymes, E2 binding enzymes, E3 ligases and deubiquitinases. Deubiquitinases can specifically hydrolyze ubiquitin molecules from target proteins, reverse the ubiquitination process, and play an important role in ubiquitination modification. Due to the complexity of the types and functions of deubiquitinases, the role of deubiquitinases in iCCA and the various mechanisms involved still need to be further explored. Evidence shows that the expression of many deubiquitinases changes in tumors and is closely related to the occurrence and development of tumors. Therefore, studying the molecular mechanism of the development of iCCA from the perspective of deubiquitinases has important clinical research value and may provide a new target for the treatment of iCCA.

Protein ubiquitination modification and deubiquitination are dynamic and reversible processes [5]. Deubiquitinase is an important regulator of the ubiquitin proteasome system. The dynamic balance between the two maintains the normal physiological function of the human body, and the imbalance between them leads to cancer and other diseases [6]. Studies have shown that there are nearly 100 deubiquitinases in cells. According to the structural similarity, mechanism of action and different catalytic subunits, deubiquitinases are divided into six main families [7], including ubiquitin carboxy-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), JAMM/MPN domain-associated metallopeptidases (JAMMs), ovarian-tumor proteases (OTUs), Machado–Joseph disease protein domain proteases, and the recently discovered monocyte chemotactic protein-induced protein (MCPIP) family.

OTUB2 is an important member of the OTU family. It is a dihydroubiquitinase that was first found among ovarian tumor-related genes in Drosophila melanogaster. It can participate in a variety of biological activities of the body [8,9], including inhibition of virus-induced interferon regulatory factor 3 and NF-κB activation [10], improvement of the human islet β cell survival rate [11] and promotion of DNA damage repair [12]. Studies have shown that OTUB2 is abnormally active in a variety of tumor tissues and can promote the development of non-small cell lung cancer [13], thyroid papillary carcinoma [14], and liver cancer [15]. Increasing evidence shows that OTUB2 plays an important role in regulating tumorigenesis and cancer progression by deubiquitinating other proteins. Here, we demonstrate that OTUB2 acts as a regulator of the EMT and metastasis of iCCA by stabilizing the CTNNB1-ZEB1 axis.

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