Deubiquitination in cancer stem cells

the origin and progression of tumors depend on a population of cancer cells with stem properties, known as cancer stem cells (CSCs). Similar to stem cells, CSCs are able to self-renew and propagate the tumor, as well as to differentiate into a variety of cancer cell lineages, maintaining a significant degree of cellular heterogeneity within the tumors. According to this model, CSCs are responsible for tumor initiation, progression, metastasis and therapy resistance [1]. Among the multiple tumor types from which CSCs have been isolated and characterized, colorectal cancer stands out as a paradigmatic example of neoplasia in which CSCs represent the cancer cell population responsible for tumor progression and recurrence [2]. Stemness induction and maintenance involves multiple cellular pathways in whose regulation the ubiquitin-proteasome system plays a critical role [3]. Protein ubiquitination status is regulated by deubiquitinases or DUBs, a large group of proteases with the ability to hydrolyze the peptide or isopeptide bonds that link the C-terminal group of ubiquitin to the ɛ-amino group of lysine side chains of target proteins [4]. The human genome encodes at least 100 DUBs that are classified into six families according to sequence and structural similarities: ubiquitin-specific proteases (USPs), ubiquitin carboxy-terminal hydrolases (UCHs), ovarian-tumor proteases (OTUs), Machado-Joseph disease protein domain proteases (MJDs), JAMM/MPN domain-associated metallopeptidases (JAMMs) and monocyte chemotactic protein-induced protein (MCPIP) family [5]. The USPs constitute the largest family of DUBs described to date, with more than 50 members [6]. Over the last few years, numerous reports have described the implication of members of this protease family in multiple biological processes that are frequently altered in cancer. Thus, mutations and changes in the expression levels of many USPs have been associated with tumor progression [5]. However, the oncologic relevance of many USPs and their implication in CSC biology remained largely un-explored. By analyzing transcriptional data from intestinal epithelial cells, we have recently demonstrated that USP54, a previously uncharacterized deubiquitinase, is overexpressed in colorectal CSCs [7]. Furthermore, we Editorial have found that USP54 downregulation in colon cancer cells decreases their proliferation, colony formation capacity, invasiveness, and tumorigenicity when injected into immunodeficient mice, suggesting that USP54 could promote colorectal carcinoma through the regulation of stem cell properties. The generation of gain-and loss-of-function animal models has contributed to clarify the relative importance of individual USPs in health and disease. Therefore, to further evaluate the in vivo role of USP54 in cancer, we generated mutant mice …