Chromosomal regions associated with prostate cancer risk localize to lamin B-deficient microdomains and exhibit reduced gene transcription.
The lamins are major determinants of nuclear shape and chromatin organization and these features are frequently altered in prostate cancer (CaP). Human CaP cell lines frequently have nuclear lobulations, which are enriched in A-type lamins but lack B-type lamins and have been defined as lamin B-deficient microdomains (LDMDs). LDMD frequency is correlated with CaP cell line aggressiveness and increased cell motility. In addition, LNCaP cells grown in the presence of dihydrotestosterone (DHT) show an increased frequency of LDMDs. The LDMDs are enriched in activated RNA polymerase II (Pol IIo) and androgen receptor (AR) and A-type lamins form an enlarged meshwork that appears to co-align with chromatin fibres and AR. Furthermore, fluorescence in situ hybridization and comparative genomic hybridization demonstrated that chromosomal regions associated with CaP susceptibility are preferentially localized to LDMDs. Surprisingly, these regions lack histone marks for transcript elongation and exhibit reduced BrU incorporation, suggesting that Pol II is stalled within LDMDs. Real-time PCR of genes near androgen response elements (AREs) was used to compare transcription between cells containing LDMDs and controls. Genes preferentially localized to LDMDs showed significantly decreased expression, while genes in the main nuclear body were largely unaffected. Furthermore, LDMDs were observed in human CaP tissue and the frequency was correlated with increased Gleason grade. These results imply that lamins are involved in chromatin organization and Pol II transcription, and provide insights into the development and progression of CaP.
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Brian T
BT
Helfand
Yuanyuan
Y
Wang
Katrin
K
Pfleghaar
Takeshi
T
Shimi
Pekka
P
Taimen
Dale K
DK
Shumaker
D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D053144:Cell Nucleus Shape; D042002:Chromatin Assembly and Disassembly; D002877:Chromosomes, Human / Q000378:metabolism*; D055028:Comparative Genomic Hybridization; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D034904:Lamin Type A / Q000378:metabolism; D034921:Lamin Type B / Q000172:deficiency* / Q000235:genetics; D061346:Laser Capture Microdissection; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism* / Q000473:pathology; D008856:Microscopy, Fluorescence; D060787:Neoplasm Grading; D009685:Nuclear Envelope / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012319:RNA Polymerase II / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D013997:Time Factors; D046888:Tissue Array Analysis; D014158:Transcription, Genetic; D014162:Transfection
C410798:AR protein, human; D034904:Lamin Type A; D034921:Lamin Type B; D011944:Receptors, Androgen; C440308:lamin C; D012319:RNA Polymerase II