The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers

Zhang, Liyong; Anglesio, Michael S.; O’Sullivan, Maureen; Zhang, Fan; Yang, Ge; Sarao, Renu; Nghiem, Mai; Cronin, Shane J. F.; Hara, Hiromitsu; Melnyk, Nataliya; Li, Liheng; Wada, Teiji; Arceci, Robert J.; Sorensen, Poul H.; Penninger, Josef

doi:10.1038/nm1621

Cited by 135 publications

(213 citation statements)

References 42 publications

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“…HACE1 is frequently downregulated in human tumors. 30,31 Methylation of HACE1 has been identified in gastric and colorectal cancers and its expression is markedly reduced in nasal type extranodal NK/T-cell lymphoma. 32 Recently, the 6q21-22 region, which contains HACE1, has been confirmed as a celiac disease susceptibility locus (possibly mutated).…”

Section: Discussionmentioning

confidence: 99%

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

et al. 2015

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Enteropathy-associated T-cell lymphoma (EATL) is a rare primary T-cell lymphoma of the digestive tract. EATL is classified as either Type I, which is frequently associated with and thought to arise from celiac disease and is primarily observed in Northern Europe, and Type II, which occurs de novo and is distributed all over the world with predominance in Asia. The pathogenesis of EATL in Asia is unknown. We aimed to clarify the histological and genomic profiles of EATL in Japan in a homogeneous series of 20 cases. The cases were characterized by immunohistochemistry, high-resolution oligonucleotide microarray, and fluorescence in situ hybridization (FISH) at five different loci: 1q21.3 (CKS1B), 6q16.3 (HACE1), 7p22.3 (MAFK), 9q33.3 (PPP6C), and 9q34.3 (ASS1, CARD9) using formalin-fixed paraffin-embedded sections. The histological appearance of EATL ranged from medium-to large-sized cells in 13 cases (65%), small-to medium-sized cells in five cases (25%), and medium-sized in two cases (10%). The immunophenotype was CD2 + (60%), CD3e + (100%), CD4 + (10%), CD7 + (95%), CD8 + (80%), CD56 + (85%), TIA-1 + (100%), Granzyme B + (25%), T-cell receptor (TCR)β + (10%), TCRγ + (35%), TCRγδ + (50%), and double negative for TCR (six cases, 30%). All cases were EBER − . The genomic profile showed recurrent copy number gains of 1q32. 3, 4p15.1, 5q34, 7q34, 8p11.23, 9q22.31, 9q33.2, 9q34.13, and 12p13.31, and losses of 7p14.1. FISH showed 15 patients (75%) with a gain of 9q34.3 with good correlation with array comparative genomic hybridization. EATL in Japan is characterized by non-monomorphic cells with a cytotoxic CD8 + CD56 + phenotype similar to EATL Type II. The genomic profile is comparable to EATL of Western countries, with more similarity to Type I (gain of 1q and 5q) rather than Type II (gain of 8q24, including MYC). The 9q34.3 gain was the most frequent change confirmed by FISH irrespective of the cell origin of αβ-T-cells and γδ-T-cells.

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Section: Discussionmentioning

confidence: 99%

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

et al. 2015

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“…As in Nrf2 null mice (8), tumor incidence is dramatically enhanced in Hace1 KO mice when they age or are subjected to urethane treatment and ionizing radiation (16). Because these stresses are linked to enhanced oxidative stress, we hypothesized that HACE1 may play a role in the oxidative stress response.…”

Section: Significancementioning

confidence: 96%

“…Homologous to the E6-AP Carboxyl Terminus (HECT) domain and Ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) is a tumor suppressor that is inactivated in human Wilms' tumor and other cancers (15,16). HACE1 is a HECT family E3 ligase (15)(16)(17) that binds to and ubiquitylates the GTPbound active form of Rac1, a Rho family GTPase (17,18).…”

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HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Rotblat

Southwell

Ehrnhoefer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Oxidative stress plays a key role in late onset diseases including cancer and neurodegenerative diseases such as Huntington disease. Therefore, uncovering regulators of the antioxidant stress responses is important for understanding the course of these diseases. Indeed, the nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidative stress response, is deregulated in both cancer and neurodegeneration. Similar to NRF2, the tumor suppressor Homologous to the E6-AP Carboxyl Terminus (HECT) domain and Ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) plays a protective role against stress-induced tumorigenesis in mice, but its roles in the antioxidative stress response or its involvement in neurodegeneration have not been investigated. To this end we examined Hace1 WT and KO mice and found that Hace1 KO animals exhibited increased oxidative stress in brain and that the antioxidative stress response was impaired. Moreover, HACE1 was found to be essential for optimal NRF2 activation in cells challenged with oxidative stress, as HACE1 depletion resulted in reduced NRF2 activity, stability, and protein synthesis, leading to lower tolerance against oxidative stress triggers. Strikingly, we found a reduction of HACE1 levels in the striatum of Huntington disease patients, implicating HACE1 in the pathology of Huntington disease. Moreover, ectopic expression of HACE1 in striatal neuronal progenitor cells provided protection against mutant Huntingtin-induced redox imbalance and hypersensitivity to oxidative stress, by augmenting NRF2 functions. These findings reveal that the tumor suppressor HACE1 plays a role in the NRF2 antioxidative stress response pathway and in neurodegeneration.

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“…D'un point de vue physiologique et physiopathologique, nos résultats soulèvent la question des relations entre l'activité E3 ligase de HACE1 vis-à-vis de Rac1 et ses propriétés de suppresseur de tumeur [9]. En effet, le gène codant HACE1 chez l'homme se trouve dans la région chromosomique 6q21 qui possède une activité avérée de suppresseur de tumeur.…”

Section: Inactivation De Hace1 Et Progression Tumoraleunclassified

Rac1 est la cible de l’activité E3 ubiquitine-ligase du suppresseur de tumeur HACE1

2012

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The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers

Cited by 135 publications

References 42 publications

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Rac1 est la cible de l’activité E3 ubiquitine-ligase du suppresseur de tumeur HACE1

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