Factor interaction analysis for chromosome 8 and DNA methylation alterations highlights innate immune response suppression and cytoskeletal changes in prostate cancer.
BACKGROUND
Alterations of chromosome 8 and hypomethylation of LINE-1 retrotransposons are common alterations in advanced prostate carcinoma. In a former study including many metastatic cases, they strongly correlated with each other. To elucidate a possible interaction between the two alterations, we investigated their relationship in less advanced prostate cancers.


RESULTS
In 50 primary tumor tissues, no correlation was observed between chromosome 8 alterations determined by comparative genomic hybridization and LINE-1 hypomethylation measured by Southern blot hybridization. The discrepancy towards the former study, which had been dominated by advanced stage cases, suggests that both alterations converge and interact during prostate cancer progression. Therefore, interaction analysis was performed on microarray-based expression profiles of cancers harboring both alterations, only one, or none. Application of a novel bioinformatic method identified Gene Ontology (GO) groups related to innate immunity, cytoskeletal organization and cell adhesion as common targets of both alterations. Many genes targeted by their interaction were involved in type I and II interferon signaling and several were functionally related to hereditary prostate cancer genes. In addition, the interaction appeared to influence a switch in the expression pattern of EPB41L genes encoding 4.1 cytoskeleton proteins. Real-time RT-PCR revealed GADD45A, MX1, EPB41L3/DAL1, and FBLN1 as generally downregulated in prostate cancer, whereas HOXB13 and EPB41L4B were upregulated. TLR3 was downregulated in a subset of the cases and associated with recurrence. Downregulation of EPB41L3, but not of GADD45A, was associated with promoter hypermethylation, which was detected in 79% of carcinoma samples.


CONCLUSIONS
Alterations of chromosome 8 and DNA hypomethylation in prostate cancer probably do not cause each other, but converge during progression. The present analysis implicates their interaction in innate immune response suppression and cytoskeletal changes during prostate cancer progression. The study thus highlights novel mechanisms in prostate cancer progression and identifies novel candidate genes for diagnostic and therapeutic purposes. In particular, TLR3 expression might be useful for prostate cancer prognosis and EPB41L3 hypermethylation for its detection.
Schulz
Wolfgang A
WA
Department of Urology, Heinrich Heine University, Düsseldorf, Germany. wolfgang.schulz@uni-duesseldorf.de
Alexa
Adrian
A
Jung
Volker
V
Hader
Christiane
C
Hoffmann
Michèle J
MJ
Yamanaka
Masanori
M
Fritzsche
Sandy
S
Wlazlinski
Agnes
A
Müller
Mirko
M
Lengauer
Thomas
T
Engers
Rainer
R
Florl
Andrea R
AR
Wullich
Bernd
B
Rahnenführer
Jörg
J
D015139:Blotting, Southern; D045744:Cell Line, Tumor; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D019295:Computational Biology / Q000379:methods*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005163:Factor Analysis, Statistical; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins