The MULE/HUWE1 E3 Ubiquitin Ligase Is a Tumor Suppressor

Interaction of the oncoproteins c-MYC and MYC-interacting zinc finger protein 1 (MIZ1) enhances proliferation via transcriptional repression of cell-cycle inhibitors, including cyclin-dependent kinase inhibitor 1A (p21) and cyclin-dependent kinase inhibitor 2B (p15). MYC and MIZ1, as well as other oncogenes and the tumor suppressor p53, have been shown to be substrates of the E3 ubiquitin ligase HECT, UBA and WWE domain containing 1 (HUWE1, also known as MULE); however, it is not known whether MULE plays a direct role in tumorigenesis. Using a mouse model of RAS-driven skin carcinogenesis, Inoue and colleagues investigated the effect of selective MULE deletion in the skin epithelium and found that MULE deficiency augmented the formation of highly proliferative skin tumors. This phenotype did not require p53 or p19^ARF but was largely rescued by genetic deletion of c-MYC, suggesting that MULE-mediated tumor suppression is dependent on its regulation of c-MYC. In support of this idea, MULE decreased the stability of the c-MYC/MIZ1 complex via lysine 48-linked polyubiquitination. In contrast, MULE-deficient keratinocytes exhibited accumulation of c-MYC/MIZ1 complexes, resulting in repression of p21 and p15 transcription and enhanced cell proliferation and colony formation. Knockdown of MIZ1 was sufficient to diminish c-MYC accumulation, restore p21 and p15 expression, and partially reverse the increased proliferation in MULE-deficient keratinocytes in vitro. Furthermore, MIZ1 expression was necessary for accelerated RAS-induced xenograft tumor growth in the absence of MULE, indicating that downregulation of MIZ1 levels is critical for the antitumor effects of MULE. Although the effect of MULE deletion in human tumors remains to be determined, these results establish MULE as a tumor suppressor in vivo and suggest that its regulation of c-MYC/MIZ1 promotes cell-cycle arrest as a barrier to malignant transformation.

Inoue S, Hao Z, Elia AJ, Cescon D, Zhou L, Silvester J, et al. Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15. Genes Dev 2013;27:1101–14.