The role of HRK gene in human cancer

Nakamura, Mitsutoshi; Shimada, Kaoru; Konishi, Noboru

doi:10.1038/onc.2009.48

Cited by 35 publications

(33 citation statements)

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“…HRK is a member of the BH3-only protein family and a potent inducer of apoptosis (27). HRK expression is frequently silenced by promoter methylation in multiple cancers, and such silencing is associated with a low apoptotic index in clinical specimens (28). We have now revealed that HRK is an effector for ELF4.…”

Section: Discussionmentioning

confidence: 84%

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

et al. 2016

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ELF4 (also known as MEF) is a member of the ETS family of transcription factors. An oncogenic role for ELF4 has been demonstrated in hematopoietic malignancies, but its function in epithelial tumors remains unclear. Here, we show that ELF4 can function as a tumor suppressor and is somatically inactivated in a wide range of human tumors. We identified a missense mutation affecting the transactivation potential of ELF4 in oral squamous cell carcinoma cells. Restoration of the transactivation activity through introduction of wild-type ELF4 significantly inhibited cell proliferation in vitro and tumor xenograft growth. Furthermore, we found that ELF1 and ELF2, closely related transcription factors to ELF4, also exerted antiproliferative effects in multiple cancer cell lines. Mutations in ELF1 and ELF2, as in ELF4, were widespread across human cancers, but were almost all mutually exclusive. Moreover, chromatin immunoprecipitation coupled with high-throughput sequencing revealed ELF4-binding sites in genomic regions adjacent to genes related to cell-cycle regulation and apoptosis. Finally, we provide mechanistic evidence that the antiproliferative effects of ELF4 were mediated through the induction of HRK, an activator of apoptosis, and DLX3, an inhibitor of cell growth. Collectively, our findings reveal a novel subtype of human cancer characterized by inactivating mutations in the ELF subfamily of proteins, and warrant further investigation of the specific settings where ELF restoration may be therapeutically beneficial. Cancer Res; 76(7); 1814-24. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 84%

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

et al. 2016

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“…These genes are implicated in the suppression of the cell proliferation [44, 45] and these regulations may at least partly explain the reduced E2-mediated proliferative response observed when ERα46 is co-expressed. Although not significant, the originally identified proapoptotic HRK gene [46] also exhibited a slight tendency to be specifically regulated by the ERα46 (twofold, P = 0.09).…”

Section: Discussionmentioning

confidence: 90%

The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

et al. 2016

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BackgroundTo date, all studies conducted on breast cancer diagnosis have focused on the expression of the full-length 66-kDa estrogen receptor alpha (ERα66). However, much less attention has been paid to a shorter 46-kDa isoform (ERα46), devoid of the N-terminal region containing the transactivation function AF-1. Here, we investigated the expression levels of ERα46 in breast tumors in relation to tumor grade and size, and examined the mechanism of its generation and its specificities of coregulatory binding and its functional activities.MethodsUsing approaches combining immunohistochemistry, Western blotting, and proteomics, antibodies allowing ERα46 detection were identified and the expression levels of ERα46 were quantified in 116 ERα-positive human breast tumors. ERα46 expression upon cellular stress was studied, and coregulator bindings, transcriptional, and proliferative response were determined to both ERα isoforms.ResultsERα46 was expressed in over 70% of breast tumors at variable levels which sometimes were more abundant than ERα66, especially in differentiated, lower-grade, and smaller-sized tumors. We also found that ERα46 can be generated via internal ribosome entry site-mediated translation in the context of endoplasmic reticulum stress. The binding affinities of both unliganded and fully-activated receptors towards co-regulator peptides revealed that the respective potencies of ERα46 and ERα66 differ significantly, contributing to the differential transcriptional activity of target genes to 17β estradiol (E2). Finally, increasing amounts of ERα46 decrease the proliferation rate of MCF7 tumor cells in response to E2.ConclusionsWe found that, besides the full-length ERα66, the overlooked ERα46 isoform is also expressed in a majority of breast tumors. This finding highlights the importance of the choice of antibodies used for the diagnosis of breast cancer, which are able or not to detect the ERα46 isoform. In addition, since the function of both ERα isoforms differs, this work underlines the need to develop new technologies in order to discriminate ERα66 and ERα46 expression in breast cancer diagnosis which could have potential clinical relevance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0780-7) contains supplementary material, which is available to authorized users.

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“…This result suggests that the presence of H3K27Me3 in HRK genomic locus is dependent upon SUZ12 and the association of SUZ12 to the HRK genomic locus is specific. It has previously been demonstrated that DNA methylation contributes to HRK downregulation in certain types of cancers such as prostate (32). Thus, we treated EOC cells with 5-azacytidine (5-AzaC), a DNA demethylation drug (33), and examined the expression of HRK in these cells.…”

Section: Resultsmentioning

confidence: 99%

SUZ12 Promotes Human Epithelial Ovarian Cancer by Suppressing Apoptosis via Silencing HRK

Cai

et al. 2012

Molecular Cancer Research

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Epithelial ovarian cancer (EOC) ranks first as the cause of death for gynecological cancers in the United States. SUZ12 is a component of the polycomb repressive complex 2 (PRC2) and is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). The role of SUZ12 in EOC has never been investigated. Here we show that SUZ12 is expressed at significantly higher levels in human EOC (n=117) compared with either normal human ovarian surface epithelium (n=35, p<0.001) or fallopian tube epithelium (n=15, p<0.001). There is a positive correlation between expression of SUZ12 and EZH2 in human EOC (p<0.001). In addition, expression of SUZ12 positively correlates with Ki67, a marker of cell proliferation (p<0.001), and predicts shorter overall survival (p=0.0078). Notably, knockdown of SUZ12 suppresses the growth of human EOC cells in vitro and in vivo in both orthotopic and subcutaneous xenograft EOC models. In addition, SUZ12 knockdown decreases the levels of H3K27Me3 and triggers apoptosis of human EOC cells. Mechanistically, we identified HRK, a pro-apoptotic gene, as a novel SUZ12 target gene, and demonstrated that HRK upregulation mediates apoptosis induced by SUZ12 knockdown in human EOC cells. In summary, we show that SUZ12 promotes the proliferation of human EOC cells by inhibiting apoptosis and HRK is a novel SUZ12 target gene whose upregulation contributes to apoptosis induced by SUZ12 knockdown.

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The role of HRK gene in human cancer

Cited by 35 publications

References 35 publications

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

SUZ12 Promotes Human Epithelial Ovarian Cancer by Suppressing Apoptosis via Silencing HRK

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