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The E3 Ligase HACE1 Is a Critical Chromosome 6Q21 Tumor Suppressor Involved in Multiple Cancers

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The E3 Ligase HACE1 Is a Critical Chromosome 6Q21 Tumor Suppressor Involved in Multiple Cancers ARTICLES The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers Liyong Zhang1,2,5, Michael S Anglesio3,5, Maureen O’Sullivan3, Fan Zhang3, Ge Yang2, Renu Sarao1,2, Mai P Nghiem1,2, Shane Cronin1, Hiromitsu Hara1, Nataliya Melnyk3, Liheng Li3, Teiji Wada1, Peter P Liu2, Jason Farrar4, Robert J Arceci4, Poul H Sorensen3 & Josef M Penninger1 Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor http://www.nature.com/naturemedicine suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers. Human cancer mapping studies for cataloguing regions of genomic RESULTS loss of heterozygosity (LOH) have defined a large number of LOH HACE1 is epigenetically inactivated in human Wilms’ tumor regions that are common to multiple human cancers1. Deletions or We originally identified the HACE1 gene by cloning the chromosome Nature Publishing Group Group Nature Publishing 7 LOH on human chromosome 6q21 have been widely reported in 6q21 breakpoint of a t(6;15)(q21;q21) translocation in a human human malignancies, including carcinomas of the breast, ovary and Wilms’ tumor12. This rearrangement was associated with marked 200 2–6 © prostate, as well as in leukemias and lymphomas , and it has been downregulation of HACE1 mRNA and protein expression compared hypothesized that this region harbors one or more tumor-suppressor to normal kidney from the same person, even though the transloca- genes7. The key tumor-suppressor gene(s) on chromosome 6q21 have tion did not directly disrupt the HACE1 locus. Fluorescence in situ not been identified to date. hybridization (FISH) analysis confirmed that HACE1 localizes to a We previously identified a t(6;15)(q21;q21) translocation in a region of human chromosome 6q21 that is disrupted in this individual sporadic Wilms’ tumor8. Wilms’ tumors account for over 90% of (Fig. 1a). To extend these findings, we analyzed HACE1 expression in pediatric kidney tumors and 6% of all childhood cancers9. Involve- 26 individuals with Wilms’ tumor. HACE1 levels were markedly ment of the 6q21 region has previously been reported in Wilms’ reduced to virtually undetectable in 20 (77%) of the 26 Wilms’ tumors tumor, including t(5;6)(q21;q21) and t(2;6)(q35;q21) rearrange- compared to patient-matched normal kidney, at both the mRNA ments9–11. We therefore characterized the chromosome 6q21 break- (Supplementary Fig. 1a online) and the protein levels (Fig. 1b). point and found that it mapped directly adjacent to a 6q21 gene12.The Sequencing of all 24 exons of the HACE1 gene plus intron-exon encoded protein has a previously unreported domain architecture, boundaries in tumor and matching normal tissue did not detect consisting of six ankyrin protein-protein interaction motifs with mutations or deletions affecting HACE1 in any of the cases of Wilms’ sequence similarity to those of INK4A, linked to a C-terminal tumor (data not shown). We therefore assessed whether epigenetic homologous to E6-associating protein carboxyl terminus (HECT) inactivation of HACE1 might underlie the observed downregulation. ubiquitin-protein ligase domain13. We designated this gene HECT There are three CpG islands (the most common sites of DNA domain and ankyrin repeat–containing E3 ubiquitin-protein ligase 1, hypermethylation in tumors14) associated with the HACE1 locus: or HACE1.Thein vivo function of this novel HECT E3 ubiquitin CpG-88, containing the transcriptional start site, and CpG-29 and ligase was entirely unknown. CpG-177, located directly upstream of the HACE1 coding sequence12. 1Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, 1030 Vienna, Austria. 2Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada. 3British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada and the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V5Z1L3, Canada. 4Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231, USA. 5These authors contributed equally to this work. Correspondence should be addressed to P.H.S. ([email protected]) or J.M.P. ([email protected]). Received 8 September 2006; accepted 27 June 2007; published online 12 August 2007; doi:10.1038/nm1621 1060 VOLUME 13 [ NUMBER 9 [ SEPTEMBER 2007 NATURE MEDICINE ARTICLES To evaluate the association of DNA methylation with HACE1 expres- DNA methylation within these three defined CpG islands (Supple- sion in Wilms’ tumor, we used bisulfite genomic sequencing (BGS) mentary Fig. 1b online). We found no evidence for cytosine methyla- and methylation-sensitive PCR (MS-PCR) to assess the pattern of tion at CpG-88. However, both CpG-29 and CpG-177 contained DNA a b 785 015 555 728 586 520 432 N T NTNTNTNTNT NT HACE1 β-Actin 628 321 395 624 033 277 654 N T NTNTNTNTNT NT HACE1 β-Actin c CpG-177 Normal samples Tumor samples Methylation CpG position http://www.nature.com/naturemedicine Unmethylated Methylated Not present Methylation CpG position Unmethylated Methylated Not present Methylation CpG position Unmethylated Methylated Not present Nature Publishing Group Group Nature Publishing 7 CpG-29 Normal samples Tumor samples 200 d © Methylation CpG position Unmethylated Methylated Not present Methylation CpG position Unmethylated Methylated Not present Methylation CpG position Unmethylated Methylated Not present Unmethylated Methylated Not present In Clone Figure 1 Loss of HACE1 expression by epigenetic modification in human Wilms’ tumor. (a) FISH analysis. A chromosome 6q21 BAC probe containing the human HACE1 locus, 111D22 (green), was hybridized to metaphase chromosomes from a Wilms’ tumor with a t(6;15)(q21;q21) translocation. Arrows indicate genomic rearrangement of this locus. Chromosomes were stained with 4¢,6-diamidino-2-phenylindole (DAPI). Original magnification Â100. (b) HACE1 protein expression is markedly reduced to undetectable in 13 of 14 primary Wilms’ tumors (T) compared to patient-matched adjacent normal kidney (N). Protein expression was determined by western blot. b-actin is shown as a loading control. Numbers refer to individual patients. (c,d) Increased methylation at CpG-177 (c) and relative hypomethylation at CpG-29 (d) in Wilms’ tumor samples compared to paired normal kidney tissue controls. Each box corresponds to a CpG position in the genomic sequence. Colored bars represent the aggregated methylation status as assessed by bisulfite genomic sequencing (BGS) at each position: yellow, methylated; blue, unmethylated; gray, not present or not evaluable in the sequence read. Numbers below each bar indicate the total number of methylated, unmethylated and non-evaluated CpGs at each position. Aggregated normal tissues are shown at left and tumor samples at right. NATURE MEDICINE VOLUME 13 [ NUMBER 9 [ SEPTEMBER 2007 1061 ARTICLES Figure 2 Reduced HACE1 expression in multiple NT N T N T N T Melanoma Hepatocellular carcinoma human tumors and spontaneous tumor formation a c in Hace1 mutant mice. (a) HACE1 mRNA expres- sion levels in paired human tumor (T) and patient- matched normal tissue (N) arrays probed with a full-length HACE1 cDNA. (b)Chromosome6 Vulva ideogram and expanded 6q21 region illustrating previously described LOH regions in multiple human tumors. Vertical bars indicate tumor subtypes with LOH between the Breast Renal Thyroid Liver Lung adenocarcinoma Angiosarcoma polymorphic markers D6S1845 and D6S1424. I, ovarian carcinoma and benign ovarian 25 32 33, b 24 I tumors , non-Hodgkin’s lymphoma (NHL) 23 II 34 22 childhood acute lymphoblastic lymphoma , III gastric carcinoma35, T and NK cell lymphomas36, p 21 IV invasive ductal breast carcinoma37–41; V 42 12 II, pancreatic carcinoma ; III, prostate q16.3 D6S1845 carcinoma2,43; IV, central nervous system (CNS) 12 D6S1021 lymphoma44; V, sporadic endocrine pancreatic 13 HACE 1 14 D6S268 45 15 q21 Mammary carcinoma Lymphoma tumors .(c) Photomicrographs of H&E-stained HACE 1 sections showing tumors that developed 16 D6S261 q21.1 spontaneously in aged (41 year) Hace1–/– mice. 21 Melanoma: the black arrow indicates intact q 22 q22.31 epidermis and the white arrow an ulceration 23 D6S1702 overlying the dermal tumor (original magnification 24 Â100). Arrowhead in inset points to melanin q22.33 25 http://www.nature.com/naturemedicine pigment production by pleomorphic cells 26 27 q23.1 infiltrating the dermis (Â400). Hepatocellular D6S1424 Chr 6 carcinoma: effacement of normal porto-lobular
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