KDM1A triggers androgen-induced miRNA transcription via H3K4me2 demethylation and DNA oxidation.
BACKGROUND
Androgen receptor (AR) is a ligand dependent transcription factor that regulates the transcription of target genes. AR activity is closely involved in the maintenance and progression of prostate cancer. After the binding with androgen, AR moves into nucleus and binds to DNA sequence containing androgen response elements (ARE). Flavin-dependent monoamine oxidase KDM1A is necessary for AR driven transcription while the mechanism remains unclear.


METHODS
The association between androgen-dependent transcription and oxidation was tested through pharmaceutical inhibitions and siRNA knockdown of DNA oxidation repair components in prostate cancer cells. The recruitment of involved proteins and the histone methylation dynamics on ARE region was explored by chromatin immunoprecipitation (ChIP).


RESULTS
Oxidation inhibition reduced AR dependent expression of KLK3, TMPRSS2, hsa-miR-125b2, and hsa-miR-133b. And such reduction could be restored by H2 O2 treatment. KDM1A recruitment and H3K4me2 demethylation on ARE regions, which produce H2 O2 , are associated with AR targets transcription. AR targets transcription and coupled oxidation recruit 8-oxoguanine-DNA glycosylase (OGG1) and the nuclease APEX1 to ARE regions. Such recruitment depends on KDM1A, and is necessary for AR targets transcription.


CONCLUSIONS
Our work underlined the importance of histone demethylation and DNA oxidation/repairing machinery in androgen-dependent transcription. The present finds have implications for research into new druggable targets for prostate cancer relying on the cascade of AR activity regulation.
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, P.R. China.
Shu
S
Yang
Jiyuan
J
Zhang
Yalong
Y
Zhang
Xuechao
X
Wan
Congzhe
C
Zhang
Xiaohui
X
Huang
Wenhua
W
Huang
Honglei
H
Pu
Chaohan
C
Pei
Hai
H
Wu
Yan
Y
Huang
Shengdong
S
Huang
Yao
Y
Li
D000111:Acetylcysteine / Q000494:pharmacology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010293:Pargyline / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
C410798:AR protein, human; D004273:DNA, Neoplasm; D006657:Histones; D035683:MicroRNAs; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D012313:RNA; D010293:Pargyline; D056466:Histone Demethylases; C495195:KDM1A protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D017430:Prostate-Specific Antigen; D000111:Acetylcysteine
LSD1; androgen receptor; histone demethylation; miRNA; oxidation