Abstract
Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA H19H19 silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of H19 and the Huwe1-null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer. Cancer Res; 77(18); 4773-84. ©2017 AACR.
Highlights
Ubiquitination and its control of subsequent protein degradation are essential biological processes in many cells, including cancer
Huwe1 deletion impairs transformation in mouse ovary surface epithelium (MOSE) cells To determine the role of Huwe1 in ovarian cancer, we established an ovarian cancer model by transforming MOSE cells in vitro via the lentiviral expression of KRASG12D, MYC, and tp53 shRNA, which are the genes that are most frequently mutated in ovarian cancer according to the The Cancer Genome Atlas (TCGA) database
Huwe1 deletion was induced by treatment with tamoxifen, which was transformed into the active metabolite 4-OHT in vivo on day 16, when tumors were not yet clearly detectable, and on day 32, when the tumor size reached 5–8 mm in diameter (Fig. 2A)
Summary
Ubiquitination and its control of subsequent protein degradation are essential biological processes in many cells, including cancer. The specificity of these processes is regulated by the E3 ligase. The HECT family (homologous to E6-AP carboxyl terminus-type E3s) is an important class of E3 ligases, and many of its members are involved in cancer-associated processes, including apoptosis and growth arrest [1]. HUWE1 is a large HECT E3 ligase with a molecular size of 480 kDa, and its role in cancer has been the subject of debate since it was first cloned. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Zhang are the co-first authors of this article
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