The role of deubiquitinases in breast cancer

Abstract

Although growing numbers of oncoproteins and pro-metastatic proteins have been extensively characterized, many of these tumor-promoting proteins are not good drug targets, which represents a major barrier to curing breast cancer and other cancers. There is a need, therefore, for alternative therapeutic approaches to destroying cancer-promoting proteins. The human genome encodes approximately 100 deubiquitinating enzymes (DUBs, also called deubiquitinases), which are amenable to pharmacologic inhibition by small molecules. By removing monoubiquitin or polyubiquitin chains from the target protein, DUBs can modulate the degradation, localization, activity, trafficking, and recycling of the substrate, thereby contributing substantially to the regulation of cancer proteins and pathways. Targeting certain DUBs may lead to destabilization or functional inactivation of some key oncoproteins or prometastatic proteins, including non-druggable ones, which will provide therapeutic benefits to cancer patients. In breast cancer, growing numbers of DUBs are found to be aberrantly expressed. Depending on their substrates, specific DUBs can either promote or suppress mammary tumors. In this article, we review the role and mechanisms of action of DUBs in breast cancer, and discuss the potential of targeting DUBs for cancer treatment.

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

“…Second, targeting the ubiquitin pathway for regulating target protein levels, rather than for its biological activity, has emerged as a promising therapeutic strategy for cancer patients. Because many oncoproteins are subject to UBQ-dependent degradation, enhancing UBQ or targeting certain DUBs may lead to destabilization or functional inactivation of key oncoproteins, including some undruggable targets such as MYC and β-catenin (Salami and Crews, 2017; Xiao et al, 2016). A few drugs targeting the ubiquitin pathway have been approved by the U.S. Food and Drug Administration (FDA) (Huang and Dixit, 2016; Swisher et al, 2017).…”

ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer

“…Whereas lysine 63 (K63)-linked polyubiquitination alters the substrate’s subcellular localization, affects its activity, and modulates its interaction with other proteins (Chen and Sun, 2009; Pickart and Fushman, 2004), all non-K63 ubiquitin linkages can target proteins for degradation via the proteasome (Xu et al, 2009). Ubiquitination is reversed by deubiquitinating enzymes (DUBs, or deubiquitinases), a group of proteases that remove monoubiquitin or poly-ubiquitin chains from the substrate (Wilkinson, 1997; Xiao et al, 2016). EZH2 protein is subject to ubiquitin-dependent degradation by several E3 ligases, including β-TrCP, SMURF2, and FBW7 (Jin et al, 2017; Sahasrabuddhe et al, 2015; Yu et al, 2013); however, the deubiquitinase that reverses this ubiquitination is unknown.…”

Tumor suppressor OTUD3 induces growth inhibition and apoptosis by directly deubiquitinating and stabilizing p53 in invasive breast carcinoma cells

“…The ubiquitination of many proteins has been well documented to be reversed by deubiquitinating enzymes (DUBs), which belong to a superfamily of cysteine proteases and metalloproteases that cleave ubiquitin-protein bonds. The human genome encodes approximately 100 DUBs [11] that can be classi ed into the following six families: ubiquitin-speci c proteases (USPs), ubiquitin car boxy-terminal hydrolases In BC, numerous DUBs [11], including breast cancer-promoting DUBs and cancer-suppressing DUBs, are aberrantly expressed. However, only two deubiquitination enzymes can deubiquitinate and stabilize p53 [11],and USP7 (HAUSP) might represent the rst example [12].…”