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The Role of HRK Gene in Human Cancer

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The Role of HRK Gene in Human Cancer Oncogene (2009) 27, S105–S113 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc REVIEW The role of HRK gene in human cancer M Nakamura, K Shimada and N Konishi Department of Pathology, Nara Medical University School of Medicine, Nara, Japan Apoptosis regulators play one of the most critical roles in Especially, members of the Bcl-2 gene family play tumorigenesis, and an imbalance between cell proliferation critical roles in apoptotic regulation in cancer cells, not and apoptosis may contribute to tumor progression. HRK only in tumorigenesis, but also in chemotherapy- was itself originally identified as a proapoptotic gene induced cell death (Reed, 1995). induced by diminished levels of cytokine in hematopoietic The proapoptotic Bcl-2 family can be separated into cells and cultured neurons and repressed by the expression two subgroups. The first subgroup includes members of of death-repressor proteins. A few analyses of HRK multiple Bcl-2 homology (BH) domain proteins, such as protein expression in primary central nervous system Bax; these gene proteins contain several BH regions. lymphomas have been performed, and little is known The second subgroup includes proteins that share only about the epigenetic or post-transcriptional mechanisms the homologous BH3 domain, an amphipathic a-helical that may participate in HRK inactivation. Here we show segment that is necessary for triggering cell death the data on the 50-CpG methylation status, loss of (Chittenden et al., 1995). The BH3 domain inactivates heterozygosity on 12q13.1 and its association with HRK apoptosis, but apparently does not interact with the expression in human malignancies, including prostate proapoptoic proteins, Bak or Bax (Inohara et al., 1997). cancers, astrocytic tumors and primary central nervous Members of this newly described group of BH3-only system lymphomas. Aberrant methylation of CpG islands proteins—including HRK/DP5, Bim, Noxa, Bbc3/ within the promoter is an epigenetic event largely Puma, Bmf, Bad, Bik/Blk/Nbk and Bid—all share the responsible for the silencing of the HRK gene and biological function of promoting Bax-dependent apop- subsequent low apoptotic counts in our series of malig- tosis through mitochondrial release of cytochrome c and nancies. Inactivation of HRK apparently occurs in a initiation of downstream cell death programs (Puthala- substantial proportion of all tumor phenotypes and, as a kath and Strasser, 2002). Among these factors, a novel potential proapoptotic gene, HRK may contribute to the regulator of cell death, Human Hrk, and its mouse development and progression of many human cancers. homolog (DP5) (Imaizumi et al., 1997), regulates Bcl-2 Oncogene (2009) 27, S105–S113; doi:10.1038/onc.2009.48 and Bcl-xL through selective interaction with the BH3 domain (Inohara et al., 1997). Keywords: HRK; prostate cancer; glioblastoma; primary HRK, discovered by Inohara et al. (1997), was itself central nervous system lymphoma originally identified as a proapoptotic gene located at 12q13.1 and is transcriptionally regulated in various cell types (Imaizumi et al., 1999; Sanz et al., 2000), being induced within an hour after administration of cell Introduction death stimuli (Harris and Johnson, 2001). HRK also selectively interacts with survival-promoting proteins, Apoptosis plays roles in both organ development and Bcl-2 and Bcl-xL. Common to the BH3 proteins, the tissue homeostasis. Its deregulation, together with product of HRK localizes to the membranes of defective control of proliferation, contributes to critical intracellular organelles in a pattern similar to that tumor progression (Evan and Vousden, 2001; Steinbach reported earlier for Bcl-2 and Bcl-xL. HRK is preva- et al., 2002; Debatin et al., 2003). Analyses of cell lently expressed in hematopoietic tissues and cultured turnover relating to apoptosis and proliferation provide neurons (Inohara et al., 1997; Sanz et al., 2000), but has insights into tumor doubling time, prognosis and also been shown in the pancreas, liver, lung, kidney and treatment response (Zhang et al., 1998) in that high prostate (Inohara et al., 1997; Higuchi et al., 2008). The apoptotic counts have been associated with a high role of HRK in apoptosis has been described mainly in histological grade and shortened survival in a number of hematopoietic tissues and cultured neurons; transcrip- studies (Vakkala et al., 1999). This cell death program is tion of HRK is specifically induced at the mRNA known to be activated or inactivated by a variety of and protein levels after growth factor withdrawal in genes, such as Bcl-2 and Bcl-xL, Bak and Bax. these cells, leading to cell death (Sanz et al., 2000; Harris and Johnson, 2001). Levels of HRK are high in embryonic neuronal tissues that undergo apoptosis Correspondence: Professor N Konishi, Department of Pathology, (Imaizumi et al., 1997), and in cultured neurons, its Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan. expression is increased after nerve growth factor with- E-mail: [email protected] drawal or exposure to b-amyloid (Imaizumi et al., 1999). HRK inactivation in human malignancy M Nakamura et al S106 Interestingly, b-amyloid-induced apoptosis of cultured much clinically useful information for tumor develop- neurons was shown to be mediated by E2F1 (Giovanni ment, prognosis and treatment response (Nakamura et al., 2000). et al., 1997). Some limited studies have focused on Some studies have also shown that transcription of critical regulators of apoptosis (Steinbach et al., 2002; the HRK gene is under the control of the c-Jun Debatin et al., 2003), and high apoptotic counts have N-terminal kinase pathway (Harris and Johnson, been associated with high histological grade and 2001) as well as the transcriptional repressor DREAM shortened survival (Shimada et al., 2008). Activated (Sanz et al., 2002) and that apoptosis by HRK requires regulation of mitogen-activated protein kinases and the expression of Bax (Harris and Johnson, 2001). Fas-associated death domain-containing proteins affects Sunayama et al. (2004) have shown that HRK appears cell growth, proliferation, survival and progression in to be located in the mitochondria associated with p32. prostate cancers (Shimada et al., 2006). This suggests that physical and functional interaction HRK seems to be an important component in the with p32 could have a crucial role in HRK-mediated regulation of apoptosis on tumor cells and the inactiva- apoptosis. In addition, the overexpression of Bcl-2 or tion of HRK, leading to loss of HRK expression and Bcl-xL inhibits the induction of HRK and prevents subsequent low apoptotic counts—events that may be apoptosis after growth factor withdrawal (Sanz et al., relevant to the pathogenesis of prostate cancer. 2000). As enforced coexpression of HRK and the antiapoptotic protein, Bcl-2 or Bcl-xL, inhibits the Aberrant methylation of HRK in the gene promoter and death-promoting activity of HRK (Inohara et al., exon 1. DNA methylation patterns in the promoter 1997), it appears that the balance between the steady- region can be determined by methylation-specific PCR state levels of Bcl-xL or Bcl-2 and those of HRK either (Herman et al., 1996). In addition to that of many tumor suppresses or induces apoptosis. suppressor genes, transcription of HRK might be The expression of HRK in hematopoietic progenitor regulated by the promoter that is rich in CpG cell lines can be induced not only by growth factor dinucleotides. The question, however, arises as to withdrawal but also by treatment with etoposide, a whether or not a reduced HRK expression in the tumor chemotherapeutic drug that induces apoptosis. On samples can be explained solely by promoter methyla- growth factor withdrawal or treatment with certain tion of the gene. CpG islands of HRK are relatively chemotherapeutic drugs, the repressor mechanism may large, and it is not clear whether they are coordinately be released (that is, by post-translational modification or regulated with respect to hypermethylation. To address binding to a specific factor), allowing the expression of the issue, we originally designed methylated and HRK. Thus, alterations in protein form/expression may unmethylated methylation-specific PCR primers that also be a critical feature for the survival or cell death of spanned the transcription start site and translation start cancer cells, enabling them to escape apoptosis resulting site for both promoter and exon 1 sequence (Nakamura from the DNA damage caused by chemotherapeutic et al., 2005b, 2006; Higuchi et al., 2008). Methylation of drugs and/or radiotherapy (Zhang et al., 2000). The loss the HRK promoter was detected in 0, 14, 38, 100 and of HRK expression and the underlying mechanism(s) of 25% of cancers graded as Gleason score (GS), downregulation, however, have not been widely exam- respectively (Table 1 and Figure 1). Detectable exon 1 ined in human malignancies. methylation was marginally more frequent in lower- In this text, we reviewed the 50-CpG methylation grade lesions; however, methylation of exon 1 occurred status, loss of heterozygosity (LOH) on 12q13.1 and its at the same frequency as promoter methylation in association with HRK expression in human malignan- higher-grade cancers. In comparison, none of the 30 cies, including prostate cancer, astrocytic tumor and samples of normal epithelial or stromal tissues from primary central nervous system lymphoma. areas adjacent to the tumors showed methylation in either gene region probed. HRK alteration in human malignancies Detection of HRK mRNA by reverse transcription PCR and immunohistochemistry. Although transcripts for Prostate cancer HRK were retrieved in the majority of normal controls In western countries, prostate cancer is the most and lower-grade prostate cancers, PCR products corre- common malignancy and the second leading cause of sponding to HRK were less infrequently found in high- cancer death in men (Nelson et al., 2003). Various grade cancers (Table 1 and Figure 1).
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