Expression of class I histone deacetylases indicates poor prognosis in endometrioid subtypes of ovarian and endometrial carcinomas.

Histone deacetylase (HDAC) inhibitors are an emerging class of targeted cancer therapeutics, and little is known about HDAC expression in gynecologic malignancies. Therefore, we tested the hypothesis whether high-level expression of class 1 HDACs (HDAC1, 2, and 3) is associated with clinically distinct subsets of ovarian and endometrial carcinomas. Expression was assessed by immunohistochemistry in a population-based cohort of 465 ovarian and 149 endometrial carcinomas and correlated with clinicopathologic parameters. Each of the HDACs was expressed at high levels in most ovarian (HDAC1, 61%; HDAC2, 93%; HDAC3, 84%) and endometrial (HDAC1, 61%; HDAC2, 95%; HDAC3, 83%) carcinomas. Further, 55% and 56% of ovarian and endometrial carcinomas, respectively, expressed all three HDACs at high levels. Such cases were less common among endometrioid subtypes of ovarian and endometrial carcinomas (36% and 52% positive cases, respectively) compared with high-grade serous subtypes (64 and 69%, respectively, P < .001). High-level expression of all three HDACs is associated with a poor prognosis in ovarian endometrioid carcinomas (hazard ratio, 6.7; 95% confidence interval, 1.9-23.3). The independent prognostic information and the overall high rate of expression for class I HDACs suggest that these targets should be explored as predictive factors in ovarian and endometrial carcinomas prospectively.

[1]  A. Parwani.  Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma , 2009 .

[2]  Nhu Le,et al.  Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. , 2008, Human pathology.

[3]  W. Weichert,et al.  Class I Histone Deacetylase Expression Has Independent Prognostic Impact in Human Colorectal Cancer: Specific Role of Class I Histone Deacetylases In vitro and In vivo , 2008, Clinical Cancer Research.

[4]  M. Kohno,et al.  Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross‐resistance to a wide range of DNA‐damaging drugs , 2008, Cancer science.

[5]  Carsten Denkert,et al.  Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. , 2008, The Lancet. Oncology.

[6]  W. Weichert,et al.  Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy , 2008, British Journal of Cancer.

[7]  Jee H Jung,et al.  A natural histone deacetylase inhibitor, Psammaplin A, induces cell cycle arrest and apoptosis in human endometrial cancer cells. , 2008, Gynecologic oncology.

[8]  Minoru Toyota,et al.  Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer , 2007, Proceedings of the National Academy of Sciences.

[9]  D. Huntsman,et al.  Kisspeptin and GPR54 immunoreactivity in a cohort of 518 patients defines favourable prognosis and clear cell subtype in ovarian carcinoma , 2007, BMC medicine.

[10]  H. M. Beier,et al.  Class I histone deacetylase expression in the human cyclic endometrium and endometrial adenocarcinomas. , 2007, Human reproduction.

[11]  Shi-Wen Jiang,et al.  Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment. , 2007, Gynecologic oncology.

[12]  N. Takai,et al.  Human endometrial and ovarian cancer cells: histone deacetylase inhibitors exhibit antiproliferative activity, potently induce cell cycle arrest, and stimulate apoptosis. , 2007, Current medicinal chemistry.

[13]  Matt van de Rijn,et al.  Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data , 2007, Modern Pathology.

[14]  R. Ozols,et al.  Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  P. Marks,et al.  Histone deacetylase inhibitors: molecular mechanisms of action , 2007, Oncogene.

[16]  E. Oliva,et al.  Clinicopathologic Analysis of 187 High-grade Endometrial Carcinomas of Different Histologic Subtypes: Similar Outcomes Belie Distinctive Biologic Differences , 2007, The American journal of surgical pathology.

[17]  J. Mariadason,et al.  Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth: Implications for therapy , 2007, Cancer biology & therapy.

[18]  Shi-Wen Jiang,et al.  Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells. , 2007, Gynecologic oncology.

[19]  V. L. Greenberg,et al.  In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer. , 2007, Gynecologic oncology.

[20]  C. Pérez-Plasencia,et al.  A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors , 2007, BMC Cancer.

[21]  Ronald Breslow,et al.  Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug , 2007, Nature Biotechnology.

[22]  Jessica E. Bolden,et al.  Anticancer activities of histone deacetylase inhibitors , 2006, Nature Reviews Drug Discovery.

[23]  P. Zola,et al.  Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial , 2006, British Journal of Cancer.

[24]  L. Aaltonen,et al.  A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition , 2006, Nature Genetics.

[25]  R. Ohlinger,et al.  Comparative evaluation of the treatment efficacy of suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer cell lines and primary ovarian cancer cells from patients , 2006, BMC Cancer.

[26]  S. Hauptmann,et al.  Ezrin expression is related to poor prognosis in FIGO stage I endometrioid carcinomas , 2006, Modern Pathology.

[27]  K. Novak.  Cold–cancer link , 2006, Nature Reviews Cancer.

[28]  Peter A. Jones,et al.  Epigenetic therapy of cancer: past, present and future , 2006, Nature Reviews Drug Discovery.

[29]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[30]  E. Hammond,et al.  Histone deacetylase inhibitors induce G2-checkpoint arrest and apoptosis in cisplatinum-resistant ovarian cancer cells associated with overexpression of the Bcl-2–related protein Bad , 2005, Molecular Cancer Therapeutics.

[31]  H. M. Beier,et al.  Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis , 2005, Breast Cancer Research and Treatment.

[32]  N. Kawamata,et al.  Human ovarian carcinoma cells: Histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis , 2004, Cancer.

[33]  H. Koeffler,et al.  Histone Deacetylase Inhibitors Have a Profound Antigrowth Activity in Endometrial Cancer Cells , 2004, Clinical Cancer Research.

[34]  I Vergote,et al.  Large-scale genomic instability predicts long-term outcome for women with invasive stage I ovarian cancer. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[35]  M. Franchi,et al.  Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. , 2003, Journal of the National Cancer Institute.

[36]  E. Hammond,et al.  Cell cycle blockade and differentiation of ovarian cancer cells by the histone deacetylase inhibitor trichostatin A are associated with changes in p21, Rb, and Id proteins. , 2002, Molecular cancer therapeutics.

[37]  K. Iwabuchi,et al.  Genetics of synchronous uterine and ovarian endometrioid carcinoma: combined analyses of loss of heterozygosity, PTEN mutation, and microsatellite instability. , 2002, Human pathology.

[38]  A. García,et al.  Molecular pathology of endometrial hyperplasia and carcinoma. , 2001, Human pathology.

[39]  P. Koper,et al.  Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. , 2000 .

[40]  P. Koper,et al.  Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial , 2000, The Lancet.