Androgen induction of the androgen receptor coactivator four and a half LIM domain protein-2: evidence for a role for serum response factor in prostate cancer.
Androgen receptor (AR) activity is critical for prostate cancer progression. Overexpression of several AR-associated coactivators has been shown to be essential for AR activation during disease progression. The stimuli and signaling pathways leading to overexpression of these coregulators, however, remain largely elusive. Here, we investigated whether androgen signaling, which demarcates critical transitions during prostate cancer disease progression, can affect coregulator expression. We found that expression of four and a half LIM domain protein-2 (FHL2), a key AR coactivator that is overexpressed in prostate cancer and associates with a poor prognosis, is induced strongly by androgens. Androgen induction of this coactivator established a feed-forward mechanism that robustly activated the AR. Stimulation of FHL2 after androgen exposure was time- and dose-dependent and relied on the presence of a functional AR. Androgen induction of FHL2 depended on active transcription of the FHL2 gene, mediated by action of serum response factor (SRF) on its proximal promoter. Loss of SRF, a transcription factor that preferentially regulates the expression of genes involved in mitogenic response and cytoskeletal organization, hampered prostate cancer cell proliferation. These results suggest a novel indirect mechanism of androgen action on FHL2 expression and provide evidence that SRF is an important determinant of AR action in prostate cancer cells.
Heemers
Hannelore V
HV
Department of Urology Research/Biochemistry, Mayo Clinic, Rochester, MN 55905, USA.
Regan
Kevin M
KM
Dehm
Scott M
SM
Tindall
Donald J
DJ
D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D026362:Serum Response Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*
D000728:Androgens; C105987:FHL2 protein, human; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D026362:Serum Response Factor; D014157:Transcription Factors