**6. DUBs and Tumor Suppressors**/**Oncogenes**

DUBs play an important role in cancer development by controlling various di fferent tumor suppressors and oncogenes. CYLD was first identified as the tumor suppressor gene for cylindromatosis [129]. Its protein expression level is downregulated in various tumor types [130,131]. CYLD plays an essential role in NF-κB [82] and c-Jun N-terminal kinase pathways [132]. Briefly, it inhibits NF-κB activation by promoting deubiquitylation of several UBQ-dependent NF-κB positive regulators, such as tumor necrosis factor receptor-associated factor 2 and the NF-κB essential modulator/IKKγ subunit [80–82]. Enhanced and/or prolonged NF-κB signaling due to reduced CYLD activity increases cellular apoptosis resistance and the chances of tumor formation [133]. USP13 also acts as a tumor suppressor through its regulation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/AKT pathway in oral squamous cell carcinoma. Overexpression of USP13 induces PTEN expression and represses the activation of AKT, glucose transporter-1, and hexokinase-2, leading to growth inhibition [84]. In an RNAi screen, USP11 was identified as a promyelocytic leukemia (PML) regulator to deubiquitinate and stabilize PML, counteracting the functions of PML. UBQ ligases RNF4 and the KLHL20-Cullin 3-Roc1 complex [83]. This complex causes suppression of PML in many cancer types [83]. PHLPP is a family of Ser/Thr protein phosphatases that serve as tumor suppressors by negatively regulating AKT. In CRC, USP46 is reported to bind to PHLPP and directly remove its polyubiquitin chains, resulting in the stabilization of PHLPP. USP46-mediated stabilization of PHLPP subsequently inhibits AKT, blocking proliferation and tumorigenesis in colon cancer cells [85].

A large number of DUBs have been reported to bind with and stabilize oncogenes, such as c-MYC. USP22 promotes deubiquitination of c-MYC in breast cancer cells, resulting in increased levels of c-MYC. Overexpression of USP22 stimulates tumorigenic activity in breast cancer cells and is closely correlated with breast cancer progression [87]. USP9X acts as an FBW7 interactor, and the loss of FBW7 has been observed in many types of human cancer [134]. USP9X antagonizes FBW7-mediated ubiquitylation and causes FBW7 stabilization. USP9X suppresses tumor formation by regulating FBW7 protein stability, which reduces c-MYC levels [89]. The degradation of the oncogene product MYC is also enhanced by USP28 [88]. An integrated genomic analysis of malignant pleural mesotheliomas uncovered somatic inactivating mutations in the tumor-suppressive nuclear DUB BAP1. BAP1 targets histones with the polycomb repressor subunit ASXL1 [86].
