**1. Introduction**

Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activities and stability. They are a heterogeneous group of cysteine proteases and metalloproteases [1] that cleave the isopeptide bond between a lysine and the C-terminus of UBQ. DUBs can also edit UBQ chains and process UBQ precursors. In addition, some DUBs can edit UBQ-like proteins and their conjugates. DUBs in the human genome can be classified into subclasses based on their UBQ-protease domains [1]: UBQ-specific proteases (USPs), which represent the largest class, otubain proteases (OTUs), UBQ C-terminal hydrolases (UCHs), Machado–Joseph disease proteases (MJDs), Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) motif proteases, and motif interacting with ubiquitin-containing novel DUB family (MINDY) [2]. In addition, some new potential DUBs without the above typical domains were currently identified, such as the monocyte chemotactic protein-induced protein (MCPIP) [3] and Zn-finger and UFSP domain protein (ZUFSP) [4]. Approximately 100 DUBs have been identified in humans. They are expressed and located in various organelles in the cell [5]: USP1 and USP7 are found in the nucleus, USP30 in the mitochondria, and USP21 and USP33 in microtubules. More examples are shown in Table 1 [5–8]. Some DUBs have higher expressions in specific tissues, such as USP3 and UCHL3 in the pancreas and lung and USP14 in the brain [5].

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**Table 1.** The sub-cellular localizations of DUBs in mammalian cells.

There has been extensive research on ubiquitination [9,10] and how DUBs regulate the deubiquitylation process and their relative functions [11]. Moreover, an increasing number of studies have uncovered the role of DUBs in cancer development [12]. Numerous informative reviews on DUBs have been published [13–18] and research on DUBs has been increasing in recent years. In this review, we aim to provide enriched content that summarizes the classical discoveries, and includes the current findings on DUBs that are related to di fferent aspects of human cancer, including proliferation, cell cycle control, apoptosis, the DNA damage response (DDR), tumor suppression, oncogenesis, and metastasis. Summarized information is shown in Table 2. Lastly, we discuss the potential of DUBs as chemotherapeutic targets for cancer treatment.