Abstract
Apoptosis regulators play one of the most critical roles in tumorigenesis, and an imbalance between cell proliferation and apoptosis may contribute to tumor progression. HRK was itself originally identified as a proapoptotic gene induced by diminished levels of cytokine in hematopoietic cells and cultured neurons and repressed by the expression of death-repressor proteins. A few analyses of HRK protein expression in primary central nervous system lymphomas have been performed, and little is known about the epigenetic or post-transcriptional mechanisms that may participate in HRK inactivation. Here we show the data on the 5′-CpG methylation status, loss of heterozygosity on 12q13.1 and its association with HRK expression in human malignancies, including prostate cancers, astrocytic tumors and primary central nervous system lymphomas. Aberrant methylation of CpG islands within the promoter is an epigenetic event largely responsible for the silencing of the HRK gene and subsequent low apoptotic counts in our series of malignancies. Inactivation of HRK apparently occurs in a substantial proportion of all tumor phenotypes and, as a potential proapoptotic gene, HRK may contribute to the development and progression of many human cancers.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG . (2001). Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 10: 687–692.
Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B et al. (1995). A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J 14: 5589–5596.
Debatin KM, Stahnke K, Fulda S . (2003). Apoptosis in hematological disorders. Semin Cancer Biol 13: 149–158.
Downward J . (1999). How BAD phosphorylation is good for survival. Nat Cell Biol 1: E33–E35.
Ehrlich M . (2002). DNA methylation in cancer: too much, but also too little. Oncogene 21: 5400–5413.
Esteller M, Corn PG, Baylin SB, Herman JG . (2001). A gene hypermethylation profile of human cancer. Cancer Res 61: 3225–3229.
Evan GI, Vousden KH . (2001). Proliferation, cell cycle and apoptosis in cancer. Nature 411: 342–348.
Giovanni A, Keramaris E, Morris EJ, Hou ST, O’Hare M, Dyson N et al. (2000). E2F1 mediates death of B-amyloid-treated cortical neurons in a manner independent of p53 and dependent on Bax and caspase 3. J Biol Chem 275: 11553–11560.
Harris CA, Johnson Jr EM . (2001). BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons. J Biol Chem 276: 37754–37760.
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93: 9821–9826.
Higuchi T, Nakamura M, Shimada K, Ishida E, Hirao K, Konishi N . (2008). HRK inactivation associated with promoter methylation and LOH in prostate cancer. Prostate 68: 105–113.
Imaizumi K, Morihara T, Mori Y, Katayama T, Tsuda M, Furuyama T et al. (1999). The cell death-promoting gene DP5, which interacts with the BCL2 family, is induced during neuronal apoptosis following exposure to amyloid beta protein. J Biol Chem 274: 7975–7981.
Imaizumi K, Tsuda M, Imai Y, Wanaka A, Takagi T, Tohyama M . (1997). Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death. J Biol Chem 272: 18842–18848.
Inohara N, Ding L, Chen S, Nunez G . (1997). Harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J 16: 1686–1694.
Kim HS, Woo DK, Bae SI, Kim YI, Kim WH . (2001). Allelotype of the adenoma-carcinoma sequence of the stomach. Cancer Detect Prev 25: 237–244.
Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC et al. (2002). The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61: 215–225; discussion 226–229.
Konishi N, Nakamura M, Ishida E, Shimada K, Mitsui E, Yoshikawa R et al. (2005a). High expression of a new marker PCA-1 in human prostate carcinoma. Clin Cancer Res 11: 5090–5097.
Konishi N, Shimada K, Ishida E, Nakamura M . (2005b). Molecular pathology of prostate cancer. Pathol Int 55: 531–539.
Konishi N, Shimada K, Nakamura M, Ishida E, Ota I, Tanaka N et al. (2008). Function of JunB in transient amplifying cell senescence and progression of human prostate cancer. Clin Cancer Res 14: 4408–4416.
Nakamura M, Konishi N, Tsunoda S, Hiasa Y, Tsuzuki T, Inui T et al. (1997). Retinoblastoma protein expression and MIB-1 correlate with survival of patients with malignant astrocytoma. Cancer 80: 242–249.
Nakamura M, Watanabe T, Klangby U, Asker C, Wiman K, Yonekawa Y et al. (2001a). p14ARF deletion and methylation in genetic pathways to glioblastomas. Brain Pathol 11: 159–168.
Nakamura M, Watanabe T, Yonekawa Y, Kleihues P, Ohgaki H . (2001b). Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C→A:T mutations of the TP53 tumor suppressor gene. Carcinogenesis 22: 1715–1719.
Nakamura M, Ishida E, Shimada K, Kishi M, Nakase H, Sakaki T et al. (2005a). Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas. Lab Invest 85: 165–175.
Nakamura M, Ishida E, Shimada K, Nakase H, Sakaki T, Konishi N . (2005b). Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas. Acta Neuropathol (Berl) 110: 402–410.
Nakamura M, Ishida E, Shimada K, Nakase H, Sakaki T, Konishi N . (2006). Defective expression of HRK is associated with promoter methylation in primary central nervous system lymphomas. Oncology 70: 212–221.
Nelson WG, De Marzo AM, Isaacs WB . (2003). Prostate cancer. N Engl J Med 349: 366–381.
Obata T, Toyota M, Satoh A, Sasaki Y, Ogi K, Akino K et al. (2003). Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer. Clin Cancer Res 9: 6410–6418.
Puthalakath H, Strasser A . (2002). Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 9: 505–512.
Reed JC . (1995). Bcl-2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 9: 451–473.
Sanz C, Benito A, Inohara N, Ekhterae D, Nunez G, Fernandez-Luna JL . (2000). Specific and rapid induction of the proapoptotic protein Hrk after growth factor withdrawal in hematopoietic progenitor cells. Blood 95: 2742–2747.
Sanz C, Horita M, Fernandez-Luna JL . (2002). Fas signaling and blockade of Bcr-Abl kinase induce apoptotic Hrk protein via DREAM inhibition in human leukemia cells. Haematologica 87: 903–907.
Sasaki Y, Morimoto I, Ishida S, Yamashita T, Imai K, Tokino T . (2001). Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer. Gene Therapy 8: 1401–1408.
Shimada K, Matsuyoshi S, Nakamura M, Ishida E, Konishi N . (2005). Phosphorylation status of Fas-associated death domain-containing protein (FADD) is associated with prostate cancer progression. J Pathol 206: 423–432.
Shimada K, Nakamura M, Ishida E, Higuchi T, Yamamoto H, Tsujikawa K et al. (2008). Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer. Cancer Sci 99: 39–45.
Shimada K, Nakamura M, Ishida E, Konishi N . (2006). Molecular roles of MAP kinases and FADD phosphorylation in prostate cancer. Histol Histopathol 21: 415–422.
Steinbach JP, Supra P, Huang HJ, Cavenee WK, Weller M . (2002). CD95-mediated apoptosis of human glioma cells: modulation by epidermal growth factor receptor activity. Brain Pathol 12: 12–20.
Sunayama J, Ando Y, Itoh N, Tomiyama A, Sakurada K, Sugiyama A et al. (2004). Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p32. Cell Death Differ 11: 771–781.
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . (1999). CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96: 8681–8686.
Vakkala M, Lahteenmaki K, Raunio H, Paakko P, Soini Y . (1999). Apoptosis during breast carcinoma progression. Clin Cancer Res 5: 319–324.
Wistuba II, Tang M, Maitra A, Alvarez H, Troncoso P, Pimentel F et al. (2001). Genome-wide allelotyping analysis reveals multiple sites of allelic loss in gallbladder carcinoma. Cancer Res 61: 3795–3800.
Zhang GJ, Kimijima I, Abe R, Watanabe T, Kanno M, Hara K et al. (1998). Apoptotic index correlates to bcl-2 and p53 protein expression, histological grade and prognosis in invasive breast cancers. Anticancer Res 18: 1989–1998.
Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B . (2000). Role of BAX in the apoptotic response to anticancer agents. Science 290: 989–992.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nakamura, M., Shimada, K. & Konishi, N. The role of HRK gene in human cancer. Oncogene 27 (Suppl 1), S105–S113 (2008). https://doi.org/10.1038/onc.2009.48
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2009.48
Keywords
This article is cited by
-
Effect of Enterococcus faecalis OG1RF on human calvarial osteoblast apoptosis
BMC Oral Health (2022)
-
PVT1 signals an androgen-dependent transcriptional repression program in prostate cancer cells and a set of the repressed genes predicts high-risk tumors
Cell Communication and Signaling (2021)
-
The IMAGEN study: a decade of imaging genetics in adolescents
Molecular Psychiatry (2020)
-
Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes
Molecular Psychiatry (2020)
-
The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors
Breast Cancer Research (2016)