Visit our Expo - Redox and Inflammation signaling 2012

Epigenetic Regulation of Stem Cell Maintenance Genes in Prostate Carcinoma
Michèle J. Hoffmann, Mirko Müller, Rainer Engers*, Wolfgang A. Schulz
Urologische Klinik und Institut für Pathologie*, Heinrich-Heine-Universität Düsseldorf,
Germany
E-mail: michele.hoffmann@uni-duesseldorf.de; muellemi@uni-duesseldorf.de;
engers@med.uni-duesseldorf.de ; wolfgang.schulz@uni-duesseldorf.de;
We have previously reported that hypomethylation of LINE-1 retrotransposons is associated
with the progression of prostate carcinoma. As in other cancers, causes and consequences of
this alteration are not understood. Most likely, retrotransposon hypomethylation in cancer
cells is related to a global change in chromatin structure that interacts with alterations in DNA
methylation in a mutual fashion, i.e. altered expression of chromatin regulator proteins could
alter DNA methylation and/or vice versa. In particular, some genes contributing to the stem
cell character of germ cells and early embryonic cells appear to be controlled by DNA
methylation, but also influence chromatin structure and DNA methylation in turn, e.g. the
BMI1 polycomb gene and CTCFL/BORIS. Altered expression of these genes has been
postulated to occur in many human cancers. We have therefore investigated their expression
and relationship to DNA methylation in prostate cancer.
In primary prostate cancer tissues, expression of polycomb EZH2 and BMI1 mRNAs was on
average increased and decreased, respectively. Expression of CTCFL was increased in a small
number of the cases and OCT4 was slightly diminished. No significant association with
overall DNA methylation changes in prostate cancers was observed. However, CTCFL as
well as OCT4 were less methylated in testes than in somatic cells and accordingly expressed
much more strongly. Additional experiments using DNA methylation inhibitors showed DNA
methylation to represent the essential mechanism for control of CTCFL expression, whereas
OCT4 down-regulation was more dependent on other factors. No significant changes in DNA
methylation of these two genes were found in prostate cancers, but OCT4 was
hypomethylated in testicular cancers.
Taken together, our results argue against a general reactivation of the investigated chromatin
regulators in prostate cancer, with the known exception of EZH2. Since we have investigated
bulk primary tumors, it remains of course possible that such a reactivation occurs in a small
subset of the tumor cells or in metastases.
Funded by the Deutsche Krebshilfe.
Recent Publications
Schulz WA: Molecular Biology of Human Cancers. An Advanced Student‘s Textbook. Springer, 2005
Maas S, Warskulat U, Steinhoff C, Mueller W, Grimm MO, Schulz WA, Seifert HH (2004) Decreased FAS
expression in advanced stage bladder cancer is not related to p53 status. Urology 63, 392-397
Cronauer MV, Schulz WA, Burchardt T, Ackermann R, Burchardt M (2004) Inhibition of p53 function
diminishes androgen receptor-mediated signaling in prostate cancer cell lines. Oncogene 23, 3541-3549.
Betz B, Florl AR, Seifert HH, Dall P, Schulz WA, Niederacher D (2004) DHPLC as a reliable high-throughput
pre-screening method for aberrant promoter methylation in cancer. Hum. Mutat. 23, 612-620
Zhang J, Zotz RB, Li Y, Wang R, Kiel S, Schulz WA, Wen D, Chen Z, Zhang L, Wang S, Gabbert HE, Sarbia
M (2004) Methylenetetrahydrofolate reductase C677T polymorphism and predisposition towards esophageal
squamous cell carcinoma in a German Caucasian and a northern Chinese population. J. Cancer Res. Clin.
Oncol. 130, 574-580
Florl AR, Steinhoff C, Müller M, Seifert HH, Hader C, Engers R, Ackermann R, Schulz WA (2004) Coordinate
hypermethylation at specific sites in prostate carcinoma precedes LINE-1 hypomethylation. Brit. J. Cancer 91,
985-994
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