Gene Summary

Gene:HACE1; HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1
Aliases: SPPRS
Summary:This gene encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase. The encoded protein is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. The protein is a potential tumor suppressor and is involved in the pathophysiology of several tumors, including Wilm's tumor. [provided by RefSeq, Mar 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase HACE1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (20)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Single Nucleotide Polymorphism
  • Tumor Suppressor Gene
  • Polymerase Chain Reaction
  • Up-Regulation
  • Oligonucleotide Array Sequence Analysis
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • Lymphoma, Extranodal NK-T-Cell
  • HACE1
  • Wilms Tumour
  • Case-Control Studies
  • CGH
  • Childhood Cancer
  • Adolescents
  • Neoplasm Proteins
  • Neuroblastoma
  • DNA Methylation
  • Base Sequence
  • Translocation
  • Infant
  • Gene Expression Profiling
  • rho GTP-Binding Proteins
  • Messenger RNA
  • Ubiquitin-Protein Ligases
  • Genome-Wide Association Study
  • Apoptosis
  • Staging
  • Tumor Suppressor Proteins
  • Genetic Predisposition
  • Signal Transduction
  • Cell Proliferation
  • Genotype
  • RNA Interference
  • Gene Expression
  • CpG Islands
  • Chromosome 6
  • rac1 GTP-Binding Protein
  • Natural Killer Cells
  • Mutation
  • Kidney Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Wilms TumourHACE1 and Wilms Tumour View Publications7
NeuroblastomaHACE1 and NeuroblastomaPrognostic
In a genome-wide association study (GWAS) of 2,817 neuroblastoma cases and 7,473 controls (Diskin et al 2012) found a HACE1 polymorphism (rs4336470) was associated with neuroblastoma, and also low HACE1 expression was a significant prognostic factor. In a subsequent large GWAS study (Capasso et al, 2013) also found HACE1 polymorphisms associated with neuroblastoma.
View Publications4

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HACE1 (cancer-related)

Haruta M, Arai Y, Okita H, et al.
Combined Genetic and Chromosomal Characterization of Wilms Tumors Identifies Chromosome 12 Gain as a Potential New Marker Predicting a Favorable Outcome.
Neoplasia. 2019; 21(1):117-131 [PubMed] Free Access to Full Article Related Publications
To identify prognostic factors, array CGH (aCGH) patterns and mutations in WT1 and 9 other genes were analyzed in 128 unilateral Wilms tumors (WTs). Twenty patients had no aCGH aberrations, and 31 had WT1 alterations [silent and WT1 types: relapse-free survival (RFS), 95% and 83%, respectively]. Seventy-seven patients had aCGH changes without WT1 alterations (nonsilent/non-WT1 type) and were subtyped into those with or without +12, 11q-, 16q-, or HACE1 loss. RFS was better for those with than those without +12 (P = .010) and worse for those with than those without 11q-, 16q-, or HACE1 loss (P = .001, .025, or 1.2E-04, respectively). Silent and WT1 type and 8 subtype tumors were integrated and classified into 3 risk groups: low risk for the silent type and +12 subgroup; high risk for the no +12 plus 11q-, 16q-, or HACE1 loss subgroup; intermediate risk for the WT1 type and no +12 plus no 11q-, 16q-, or HACE1 loss subgroup. Among the 27 WTs examined, the expression of 146 genes on chromosome 12 was stronger in +12 tumors than in no +12 tumors, while that of 10 genes on 16q was weaker in 16q- tumors than in no 16q- tumors. Overexpression in 75 out of 146 upregulated genes and underexpression in 7 out of 10 downregulated genes correlated with better and worse overall survival, respectively, based on the public database. +12 was identified as a potential new marker predicting a favorable outcome, and chromosome abnormalities may be related to altered gene expression associated with these abnormalities.

Jia W, Deng Z, Zhu J, et al.
Association Between HACE1 Gene Polymorphisms and Wilms' Tumor Risk in a Chinese Population.
Cancer Invest. 2017; 35(10):633-638 [PubMed] Related Publications
Wilms' tumor is one of the most common solid tumors of childhood; however, the genetic basis underlying the majority of cases remains largely unknown. HACE1 is a putative Wilms' tumor susceptibility gene. We investigated the association between five HACE1 gene polymorphisms and Wilms' tumor susceptibility in a Chinese population consisting of 145 patients and 531 controls. We found a significant association between HACE1 rs9404576 polymorphism and decreased Wilms' tumor risk. No significant association was detected for other polymorphisms in the overall analysis. Our results indicated that HACE1 rs9404576 polymorphism may be associated with Wilms' tumor susceptibility in the Chinese population.

Bouzelfen A, Kora H, Alcantara M, et al.
Heterogeneous epigenetic regulation of HACE1 in Burkitt- Lymphoma-derived cells.
Leuk Res. 2017; 60:53-57 [PubMed] Related Publications
We examined the consequences of 3-deazaneplanocin A (DZNep) on HACE1 expression in human Burkitt- Lymphoma-derived cells to investigate fundamental molecular mechanisms that control its expression. We treated the human Burkitt- Lymphoma-derived cells lines Ramos and Raji with DZNep and examined HACE1 mRNA expression by RT-PCR. We also studied the effect of DZNep on the methylation of lysine 9 and 27 of histone 3 (H3K27me3 and H3K9me2) associated with the CpG88 and CpG177 islands of the HACE1 promoters by chromatin immunoprecipitation and quantitative PCR. CpG88 (hypomethylated) of the HACE1 promoter was enriched for histone marks H3K27me3 and H3K9me2 whereas CpG177 (hypermethylated) was only enriched for H3K9me2. DZNep treatment increased HACE1 gene expression which was further increased by the addition of trichostatine A (TSA), a promising therapeutic compound for the treatment of human B-Lymphoma. Histone methylation (both H3K9me2 and H3K27me3) of the HACE1 promoter concomitantly decreased. Our experiments suggest that HACE1 can be downregulated by methylation of its promoter region chromatin (H3K27me3 and H3K9me2), making HACE1 a potential target for DZNep combined with TSA. These results highlight the heterogeneity of HACE1 regulation in B-lymphoma and suggest that successful drug-induced restoration of epigenetically silenced tumor suppressor genes will require accurate characterization of cell type- and locus-specific gene silencing mechanisms.

Gao ZF, Wu YN, Bai ZT, et al.
Tumor-suppressive role of HACE1 in hepatocellular carcinoma and its clinical significance.
Oncol Rep. 2016; 36(6):3427-3435 [PubMed] Related Publications
An increasing body of evidence suggests that downregulation or deletion of HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) gene plays an important role in the occurrence, invasion and metastasis process in many human malignancies and is closely related to prognosis. However, sparse evidence exists concerning the precise function and clinical significance of HACE1 in hepatocellular carcinoma (HCC). In the present study, we investigated the expression pattern of HACE1 in HCC tissues and cell lines, and determined the potential functions of HACE1 in HCC cell lines and evaluated the relationships between HACE1 expression and clinicopathological characteristics. Protein and mRNA expression levels of HACE1 in human HCC tissues and cell lines were examined by western blot analysis, quantitative real‑time polymerase chain reaction and immunohistochemical (IHC) analyses. IHC was used to analyze the correlations between HACE1 expression and clinicopathological features. HACE1 was upregulated in SMCC7721 cells by transfection with pcDNA3.1-HACE1 and Huh7 cells were transfected with siRNA targeting HACE1 for downregulation. Cell Counting Κit-8, Transwell and wound healing assays were performed to investigate the effects of the overexpression and knockdown of HACE1 on cellular proliferation and migration. The results revealed that HACE1 expression was lower in the HCC tissues and cell lines at the mRNA and protein levels compared to levels noted in the matched non‑tumor tissues and the normal liver cell line L02. Knockdown of HACE1 in Huh7 cells accelerated cell proliferation and migration (P<0.05), and overexpression of HACE1 in SMCC7721 cells was found to decrease the capacity for proliferation and migration (P<0.01). The results of IHC suggested that the HACE1 expression level was closely related to the serum AFP level, tumor differentiation and vascular invasion (P<0.05). Patients with low HACE1 expression levels exhibited poorer overall survival and HACE1 was found to be an independent prognostic factor for survival. In conclusion, as a tumor suppressor, HACE1 may be a valuable prognostic biomarker and potential therapeutic target for HCC treatment.

Bouzelfen A, Alcantara M, Kora H, et al.
HACE1 is a putative tumor suppressor gene in B-cell lymphomagenesis and is down-regulated by both deletion and epigenetic alterations.
Leuk Res. 2016; 45:90-100 [PubMed] Related Publications
HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1, HACE1, located on chromosome 6q, encodes an E3 ubiquitin ligase and is downregulated in many human tumors. Here, we report HACE1 as a candidate tumor suppressor gene down-regulated by a combination of deletion and epigenetic mechanisms. HACE1 deletions were observed in 40% of B-cell lymphoma tumors. Hypermethylation of the HACE1 promoter CpG177 island was found in 60% (68/111) of cases and in all tested B-cell lymphoma lines. Using HDAC inhibitors, we observed predominantly inactive chromatin conformation (methylated H3 histones H3K9me2) in HACE1 gene promoter region. We demonstrated in Ramos and Raji cells that down-regulation of HACE1 expression was associated with a significant decrease in apoptosis and an accumulation of cells in the S and G2/M phases. Our experiments indicate that HACE1 can act as a haploinsufficient tumor suppressor gene in most B-cell lymphomas and can be downregulated by deacetylation of its promoter region chromatin, which makes HACE1 a potential target for HDAC inhibitors.

Cybula M, Wieteska Ƚ, Józefowicz-Korczyńska M, et al.
New miRNA expression abnormalities in laryngeal squamous cell carcinoma.
Cancer Biomark. 2016; 16(4):559-68 [PubMed] Related Publications
BACKGROUND: Although the development of novel diagnostic and treatment strategies concerning laryngeal cancer is highly intensive, the survival rate remains virtually unchanged. Small non-coding RNAs appear to be very promising biomarkers - and so remain the focus of extensive investigation in laryngeal cancer.
OBJECTIVE: We examined the expression of five miRNA and five genes related to cancer whether they could be potential laryngeal cancer biomarkers.
METHODS: We performed an analysis in 47 patients diagnosed with laryngeal cancer. The qPCR technique was used to investigate the expression profile.
RESULTS: While miR-21-3p and miR-525-5p were found to be significantly up-regulated, miR-139-3p and miR-885-5p expression is lower in laryngeal cancer. Moreover, PIK3R1 and HACE1 were found to be also down-regulated.
CONCLUSIONS: The change in miRNA expression is frequent than the expression of other tested genes. The expression of passenger strands such as miR-21-3p and miR-139-3p, which are rarely investigated, is also significantly affected in laryngeal cancer. While PIK3R1, HACE1, miR-139-3p, and miR-885-5p may act as tumor suppressor genes in the studied tumour type, miR-21-3p and miR-525-5p seem to have oncogenic properties. Our findings suggest that miR-885-5p and PIK3R1 are the best indicators for the classification of laryngeal cancer tissue and normal mucosa.

Gao LM, Zhao S, Liu WP, et al.
Clinicopathologic Characterization of Aggressive Natural Killer Cell Leukemia Involving Different Tissue Sites.
Am J Surg Pathol. 2016; 40(6):836-46 [PubMed] Related Publications
Aggressive natural killer cell leukemia (ANKL) is a rare disease with an extremely aggressive clinical course. The etiology of ANKL is unclear with few genetic/epigenetic aberrations described to date. Moreover, misdiagnosis of ANKL is a frequent problem. Clinicopathologic characteristics of 35 retrospective cases of ANKL were investigated with the aim of improving diagnosis and to find the genetic/epigenetic aberrations associated with ANKL etiology. Because of the relatively low number of leukemic cells in the peripheral blood and bone marrow, diagnosis of ANKL can be missed; therefore, it is important to perform biopsy on solid tissues, if necessary. We describe the pathology of ANKL in the lymph nodes, bone marrow, spleen, liver, and skin, with focus on diagnosis and differentiated diagnosis. We observed young male predominance in our cohort, and the clinical course was more aggressive than reported previously. Low lactate dehydrogenase (<712 IU/L), chemotherapy or L-asparaginase administration were found to be associated with more favorable outcomes. SH2 domains of STAT5B and STAT3 also were screened for the presence of activating mutations. Moreover, CpG island methylation status of HACE1, a candidate tumor-suppressor gene, was determined in ANKL samples. We observed activating STAT5B mutations (1/5) and hypermethylation of HACE1 (3/4) in ANKL cases, suggesting that these aberrations may contribute to ANKL pathogenesis.

Goka ET, Lippman ME
Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression.
Oncogene. 2015; 34(42):5395-405 [PubMed] Free Access to Full Article Related Publications
The transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu is frequently overexpressed in DCIS but is less common in IBC, thereby suggesting additional requirements for transformation. To identify genes capable of cooperating with HER2/neu to fully transform mammary epithelial cells, we used an insertional mutagenesis screen on cells isolated from wild-type neu expressing mice and identified the E3 ligase HACE1 as HER2 cooperative tumor suppressor gene. Loss of HACE1 expression is commonly seen in clinical breast cancer data sets. HACE1 downregulation in normal human mammary epithelial cells (HMECs) results in the accumulation of the activated GTP-bound Rac1 partially transforming these cells. Overexpression of HER2 activates Rac1, which further accumulates upon HACE1 loss resulting in Rac1 hyperactivation. Although the knockdown of HACE1 or overexpression of HER2 alone in HMECs is not sufficient for tumorigenesis, HER2 overexpression combined with HACE1 downregulation fully transforms HMECs resulting in robust tumor formation. The pharmaceutical interference of Rac function abrogates the effects of HACE1 loss both in vitro and in vivo, resulting in marked reduction in tumor burden. Our work supports a critical role for HACE1 in breast cancer progression and identifies patients that may benefit from Rac-targeted therapies.

Capasso M, Diskin S, Cimmino F, et al.
Common genetic variants in NEFL influence gene expression and neuroblastoma risk.
Cancer Res. 2014; 74(23):6913-24 [PubMed] Free Access to Full Article Related Publications
The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identified single-nucleotide polymorphisms (SNP) associated with neuroblastoma at the CASC15, BARD1, LMO1, DUSP12, HSD17B12, HACE1, and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated eight additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNPs at these candidate genes were tested for association with disease susceptibility in 2,101 cases and 4,202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing, and cellular differentiation assays. The neurofilament gene NEFL harbored three SNPs associated with neuroblastoma (rs11994014: Pcombined = 0.0050; OR, 0.88; rs2979704: Pcombined = 0.0072; OR, 0.87; rs1059111: Pcombined = 0.0049; OR, 0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biologic investigations showed that ectopic overexpression of NEFL inhibited cell growth specifically in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens were associated with better overall survival (P = 0.03; HR, 0.68). Our results show that common variants of NEFL influence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and progression.

Sako N, Dessirier V, Bagot M, et al.
HACE1, a potential tumor suppressor gene on 6q21, is not involved in extranodal natural killer/T-cell lymphoma pathophysiology.
Am J Pathol. 2014; 184(11):2899-907 [PubMed] Related Publications
Extranodal natural killer-T-cell lymphoma (NKTCL) of nasal type is a malignant disorder of cytotoxic lymphocytes of natural killer or more rarely T cells, associated with clonal Epstein-Barr virus infection. NKTCL is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of NKTCL is little understood, some insight has been gained in the recent years, especially from genome-wide studies, which revealed a deletion on chromosome 6q21 in more than 50% of patients. Of interest, this deleted region contains four candidate tumor suppressor genes whose decreased expression has been confirmed at the mRNA level: PRDM1, ATG5, AIM1, and HACE1. Mutations and methylation in PRDM1, ATG5, and AIM1 have been reported in NKTCL cell lines. We investigated the involvement of HACE1 in NKTCL pathophysiology. Even though the hypermethylation of CpG-177 island located directly upstream of HACE1 locus led to down-regulation of HACE1 mRNA, the protein product was expressed at nearly normal levels and was functional in the NKTCL cell lines regardless of 6q21 deletion (and indeed no double deletion of 6q21 and no nonfunctional mutations have been reported). Furthermore, contrary to previous report, overexpression of HACE1 by transduction of recombinant protein did not affect proliferation or survival of NKTCL cell lines. We therefore conclude that HACE1 is not directly involved in NKTCL pathophysiology.

Huang Y, de Leval L, Gaulard P
Molecular underpinning of extranodal NK/T-cell lymphoma.
Best Pract Res Clin Haematol. 2013; 26(1):57-74 [PubMed] Related Publications
Peripheral NK/T-cell lymphoma (PTCL) is a heterogeneous group of uncommon hematologic malignancies with aggressive clinical course and unfavorable prognosis. Extranodal NK/T-cell lymphoma, nasal type (NKTCL) is the most common extranodal entity worldwide, with heterogeneous geographic distribution, and it is characterized by its association with EBV, a nasal or less often extranasal presentation and aggressive behavior. Recent works using array-based technologies have provided novel insights into the pathogenesis and discovered new biomarkers with diagnostic and therapeutic implications in NKTCL. Gene expression profiling identified that most of the NKTCL are derived from activated natural killer cells with distinctively high expression of granzyme H compared to other PTCLs, which might serve as a new diagnostic biomarker. Frequent deletions and promoter methylations in PRDM1, ATG5, AIM1, FOXO3, HACE1 mapping to 6q21-q25, suggest their roles as potential tumor suppressors. The deregulation of oncogenic pathways (PDGF, JAK-STAT, AKT) provides a rationale for developing targeted therapies in the future.

Sakata M, Yokomizo K, Kitamura Y, et al.
Methylation of the HACE1 gene is frequently detected in hepatocellular carcinoma.
Hepatogastroenterology. 2013; 60(124):781-3 [PubMed] Related Publications
BACKGROUND/AIMS: Recently, it has been reported that HACE1, the E3 ubiquitin ligase, is epigenetically inactivated in human Wilms' tumors and HACE 1 expression was also down-regulated in colorectal and gastric carcinomas.
METHODOLOGY: In this study, methylation status of the HACE1 gene was examined in primary carcinomas and the corresponding normal tissues derived from 27 patients with HCC using quantitative methylation-specific PCR (qMSP).
RESULTS: Methylation of the HACE1 gene was detected in 18 out of the 27 (67%) HCCs, suggesting that the methylation of HACE1 was frequently observed in HCC. The clinicopathological data were then correlated with these results. In the value of serum AFP (α-fetoprotein), a significant difference was observed (p=0.0025).
CONCLUSIONS: All stages of HCCs presented HACE1 methylation, indicating that the HACE1 gene has been methylated from the early stages of HCCs.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Capasso M, Diskin SJ, Totaro F, et al.
Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility.
Carcinogenesis. 2013; 34(3):605-11 [PubMed] Free Access to Full Article Related Publications
Several neuroblastoma (NB) susceptibility loci have been identified within LINC00340, BARD1, LMO1, DUSP12, HSD17B12, DDX4, IL31RA, HACE1 and LIN28B by genome-wide association (GWA) studies including European American individuals. To validate and comprehensively evaluate the impact of the identified NB variants on disease risk and phenotype, we analyzed 16 single nucleotide polymorphisms (SNPs) in an Italian population (370 cases and 809 controls). We assessed their regulatory activity on gene expression in lymphoblastoid (LCLs) and NB cell lines. We evaluated the cumulative effect of the independent loci on NB risk and high-risk phenotype development in Italian and European American (1627 cases and 2575 controls) populations. All NB susceptibility genes replicated in the Italian dataset except for DDX4 and IL31RA, and the most significant SNP was rs6435862 in BARD1 (P = 8.4 × 10(-15)). BARD1 showed an additional and independent SNP association (rs7585356). This variant influenced BARD1 mRNA expression in LCLs and NB cell lines. No evidence of epistasis among the NB-associated variants was detected, whereas a cumulative effect of risk variants on NB risk (European Americans: P (trend) = 6.9 × 10(-30), Italians: P (trend) = 8.55 × 10(13)) and development of high-risk phenotype (European Americans: P (trend) = 6.9 × 10(-13), Italians: P (trend) = 2.2 × 10(-1)) was observed in a dose-dependent manner. These results provide further evidence that the risk loci identified in GWA studies contribute to NB susceptibility in distinct populations and strengthen the role of BARD1 as major genetic contributor to NB risk. This study shows that even in the absence of interaction the combination of several low-penetrance alleles has potential to distinguish subgroups of patients at different risks of developing NB.

Küçük C, Hu X, Iqbal J, et al.
HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms.
Am J Pathol. 2013; 182(1):49-55 [PubMed] Free Access to Full Article Related Publications
HACE1 is an E3 ubiquitin ligase located in 6q21, the genomic region frequently deleted in natural killer (NK) cell malignancies. Here, we report HACE1 as a candidate tumor suppressor gene silenced through a combination of deletion and cytosine phosphate guanine island hypermethylation. We detected deletion of HACE1 in malignant NK cell lines (6 of 9, 67%) and primary biopsies (5 of 15, 33%) by quantitative PCR, with most of the specimen showing cytosine phosphate guanine island hypermethylation in the remaining allele, leading to low mRNA transcription. The ectopic expression of HACE1 in an HACE1-null NK cell line led to apoptosis and G2/M cell cycle arrest. Moreover, HACE1 expression was up-regulated in IL-2-activated normal NK cells and NK cells cocultured with an engineered NK cell target, K562 Clone 9.mbIL21, suggesting its role in the regulation of NK cell homeostasis. In conclusion, HACE1 is another potent tumor suppressor gene located within the 6q21 region, and loss of function of multiple tumor suppressor genes within 6q21 may be a critical determinant of NK cell lymphomagenesis.

Diskin SJ, Capasso M, Schnepp RW, et al.
Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma.
Nat Genet. 2012; 44(10):1126-30 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P=2.7×10(-11); odds ratio 1.26, 95% confidence interval (CI) 1.18-1.35) and the second within LIN28B (rs17065417; combined P=1.2×10(-8); odds ratio 1.38, 95% CI 1.23-1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P=0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.

Karube K, Nakagawa M, Tsuzuki S, et al.
Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses.
Blood. 2011; 118(12):3195-204 [PubMed] Related Publications
Oligo-array comparative genomic hybridization (CGH) and gene-expression profiling of natural killer (NK)-cell neoplasms were used in an effort to delineate the molecular pathogenesis involved. Oligo-array CGH identified two 6q21 regions that were most frequently deleted (14 of 39 or 36%). One of these regions included POPDC3, PREP, PRDM1, ATG5, and AIM1, whereas the other included LACE1 and FOXO3. All genes located in these regions, except for POPDC3 and AIM1, were down-regulated in neoplastic samples, as determined by gene-expression analysis, and were therefore considered to be candidate tumor-suppressor genes. A20 and HACE1, the well-known tumor-suppressor genes located on 6q21-23, were included as candidate genes because they also demonstrated frequent genomic deletions and down-regulated expression. The Tet-Off NK cell line NKL was subsequently established for functional analyses. Seven candidate genes were transduced into Tet-Off NKL and forced re-expression was induced. Re-expression of FOXO3 and PRDM1 suppressed NKL proliferation, but this was not the case after re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10. Furthermore, genomic analyses detected nonsense mutations of PRDM1 that led to functional inactivation in one cell line and one clinical sample. PRDM1 and FOXO3 are considered to play an important role in the pathogenesis of NK-cell neoplasms.

Huang Y, de Reyniès A, de Leval L, et al.
Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type.
Blood. 2010; 115(6):1226-37 [PubMed] Free Access to Full Article Related Publications
Biopsies and cell lines of natural killer/T-cell lymphoma, nasal type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared with peripheral T-cell lymphoma, not otherwise specified, NKTCL had greater transcript levels for NK-cell and cytotoxic molecules, especially granzyme H. Compared with normal NKcells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, Epstein-Barr Virus-induced genes, and PDGFRA. Notably, platelet-derived growth factor receptor alpha and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. Deregulation of the AKT, Janus kinase-signal transducers and activators of transcription, and nuclear factor-kappaB pathways was corroborated by nuclear expression of phosphorylated AKT, signal transducers and activators of transcription 3, and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 [1q44], IL6R [1q21.3], CCL2 [17q12], TNFRSF21 [6p12.3]). Several features of NKTCL uncovered by this analysis suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets.

Slade I, Stephens P, Douglas J, et al.
Constitutional translocation breakpoint mapping by genome-wide paired-end sequencing identifies HACE1 as a putative Wilms tumour susceptibility gene.
J Med Genet. 2010; 47(5):342-7 [PubMed] Related Publications
BACKGROUND: Localisation of the breakpoints of chromosomal translocations has aided the discovery of several disease genes but has traditionally required laborious investigation of chromosomes by fluorescent in situ hybridisation approaches. Here, a strategy that utilises genome-wide paired-end massively parallel DNA sequencing to rapidly map translocation breakpoints is reported. This method was used to fine map a de novo t(5;6)(q21;q21) translocation in a child with bilateral, young-onset Wilms tumour.
METHODS AND RESULTS: Genome-wide paired-end sequencing was performed for approximately 6 million randomly generated approximately 3 kb fragments from constitutional DNA containing the translocation, and six fragments in which one end mapped to chromosome 5 and the other to chromosome 6 were identified. This mapped the translocation breakpoints to within 1.7 kb. Then, PCR assays that amplified across the rearrangement junction were designed to characterise the breakpoints at sequence-level resolution. The 6q21 breakpoint transects and truncates HACE1, an E3 ubiquitin-protein ligase that has been implicated as a somatically inactivated target in Wilms tumourigenesis. To evaluate the contribution of HACE1 to Wilms tumour predisposition, the gene was mutationally screened in 450 individuals with Wilms tumour. One child with unilateral Wilms tumour and a truncating HACE1 mutation was identified.
CONCLUSIONS: These data indicate that constitutional disruption of HACE1 likely predisposes to Wilms tumour. However, HACE1 mutations are rare and therefore can only make a small contribution to Wilms tumour incidence. More broadly, this study demonstrates the utility of genome-wide paired-end sequencing in the delineation of apparently balanced chromosomal translocations, for which it is likely to become the method of choice.

Sakata M, Kitamura YH, Sakuraba K, et al.
Methylation of HACE1 in gastric carcinoma.
Anticancer Res. 2009; 29(6):2231-3 [PubMed] Related Publications
BACKGROUND: We recently examined the methylation status of the HACE1 gene in primary carcinomas derived from 32 patients with colorectal cancer. A significant increase was observed in the maximal tumor size of the tumors with methylated HACE1 (p=0.0304). Moreover, a trend was shown toward preferentially developing lymph node metastasis in the carcinomas with methylated HACE1 (p=0.0612), suggesting that HACE1 might present a malignant potential in colorectal cancer. These results prompted us to examine the methylation status of the HACE1 gene in gastric carcinomas.
MATERIALS AND METHODS: The methylation status of the HACE1 gene was examined in primary carcinomas and the corresponding normal tissues derived from 34 patients with gastric carcinoma using quantitative methylation-specific PCR (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated.
RESULTS: An aberrant methylation of the HACE1 gene was detected in 9 out of 34 (26%) primary gastric carcinomas. Subsequently, clinicopathological data were tested for correlation with the methylation score. A significant difference was observed in patient gender (p=0.0429).
CONCLUSION: HACE1 was frequently methylated in gastric carcinoma derived from male patients.

Hibi K, Sakata M, Sakuraba K, et al.
Aberrant methylation of the HACE1 gene is frequently detected in advanced colorectal cancer.
Anticancer Res. 2008 May-Jun; 28(3A):1581-4 [PubMed] Related Publications
BACKGROUND: It has been recently reported that HACE1, the E3 ubiquitin ligase, is epigenetically inactivated in human Wilms' tumors and HACE1 expression was also down-regulated in colon carcinomas.
MATERIALS AND METHODS: The methylation status of the HACE1 gene was examined in primary carcinomas and the corresponding normal tissues derived from 32 patients with colorectal cancer using quantitative methylation-specific PCR (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated.
RESULTS: Aberrant methylation of the HACE1 gene was detected in 9 out of the 32 (28%) primary colon carcinomas, suggesting that the aberrant methylation of HACE1 was frequently observed in colorectal cancer. The clinicopathological data were then correlated with these results. A significant increase was observed in the maximal tumor size of the methylated HACE1 tumors (p = 0.0304). Moreover, a trend was shown towards preferentially developing lymph node metastasis in the methylated HACE1 carcinomas (p = 0.0612).
CONCLUSION: HACE1 might act as a tumor suppressor in colorectal carcinomas and HACE1 methylation might present a malignant potential in colorectal cancer.

Stewénius Y, Jin Y, Ora I, et al.
High-resolution molecular cytogenetic analysis of Wilms tumors highlights diagnostic difficulties among small round cell kidney tumors.
Genes Chromosomes Cancer. 2008; 47(10):845-52 [PubMed] Related Publications
Many solid tumors exhibit characteristic gene fusions, which are reflected by balanced translocations at the cytogenetic level. These changes might be useful diagnostic and prognostic tools. In Wilms tumor (WT, nephroblastoma) no fusions genes or recurrent balanced translocations have been described thus far. To screen for cryptic balanced translocations, we have analyzed 17 renal neoplasms, histopathologically classified as WT, by a combination of G-banding, multicolor FISH, and subtelomeric FISH. This approach revealed several submicroscopic chromosomal aberrations and three different seemingly balanced translocations, resulting in a heterozygous deletion of HACE1, an EWSR1/ERG fusion, and an EWSR1/FLI1 fusion, respectively. As EWSR1 rearrangements are known to be a characteristic of Ewing tumors (ET), our findings illustrate the diagnostic problems regarding small cell kidney tumors and strongly argue for the need of adjuvant diagnostic techniques in this group of neoplasms. In summary, our genomic screening approach proved efficient in finding structural chromosomal aberrations. The fact that no recurrent translocations were found in the WTs of this study argues against the presence of a frequent pathognomonic translocation in this disease entity.

Thelander EF, Ichimura K, Corcoran M, et al.
Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia.
Leuk Lymphoma. 2008; 49(3):477-87 [PubMed] Related Publications
The study was undertaken with the aim to outline deletion patterns involving the long arm of chromosome 6, a common abnormality in lymphoproliferative disorders. Using a chromosome 6 specific tile path array, 60 samples from in total 49 cases with mantle cell lymphoma (MCL), de novo diffuse large B-cell lymphoma (DLBCL), transformed DLBCL as well as preceding follicular lymphoma (FL), and childhood acute lymphoblastic leukemia (ALL), were characterized. Twenty-six of the studied cases, representing all diagnoses, showed a 6q deletion among which 85% involved a 3 Mb region in 6q21. The minimal deleted interval in 6q21 encompasses the FOXO3A, PRDM1 and HACE1 candidate genes. The PRDM1 gene was found homozygously deleted in a case of DLBCL. Moreover, in two DLBCL cases, an overlapping homozygous deletion was identified in 6q23.3 - 24.1, encompassing the TNFAIP3 gene among others. Taken together, we refined the deletion pattern within the long arm of chromosome 6 in four different types of hematological malignances, suggesting the location of tumor suppressor genes involved in the tumor progression.

Zhang L, Anglesio MS, O'Sullivan M, et al.
The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers.
Nat Med. 2007; 13(9):1060-9 [PubMed] Related Publications
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 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.

Anglesio MS, Evdokimova V, Melnyk N, et al.
Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney.
Hum Mol Genet. 2004; 13(18):2061-74 [PubMed] Related Publications
We have analyzed the chromosome 6q21 breakpoint of a non-constitutional t(6;15)(q21;q21) rearrangement in sporadic Wilms' tumor. This identified a novel gene encoding a protein with six N-terminal ankyrin repeats linked to a C-terminal HECT ubiquitin-protein ligase domain. We therefore designated this gene HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1). HACE1 is widely expressed in human tissues, including mature and fetal kidney. We show that Hace1 protein possesses intrinsic ubiquitin ligase activity, utilizes UbcH7 as a candidate partner E2 enzyme and localizes predominantly to the endoplasmic reticulum. Although the HACE1 locus was not directly interrupted by the translocation in the index Wilms' case, its expression was markedly lower in tumor tissue compared with adjacent normal kidney. Moreover, HACE1 expression was virtually undetectable in the SK-NEP-1 Wilms' tumor cell line and in four of five additional primary Wilms' tumor cases compared with patient-matched normal kidney. We found no evidence of HACE1 mutations or deletions, but hypermethylation of two upstream CpG islands correlates with low HACE1 expression in tumor samples. Our findings implicate Hace1 as a novel ubiquitin-protein ligase and demonstrate that its expression is very low in primary Wilms' tumors.

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