The role of CREB3L4 in the proliferation of prostate cancer cells.
The incidence of prostate cancer (PC) is growing rapidly throughout the world, in probable association with the adoption of western style diets. Thus, understanding the molecular pathways triggering the development of PC is crucial for both its prevention and treatment. Here, we investigated the role of the metabolism-associated protein, CREB3L4, in the proliferation of PC cells. CREB3L4 was upregulated by the synthetic androgen, R1881, in LNCaP PC cells (an androgen-dependent cell line). Knockdown of CREB3L4 resulted in decreased androgen-dependent PC cell growth. LNCaP cells transfected with siCREB3L4 underwent G2/M arrest, with upregulation of the proteins cyclin B1, phospho-CDK1, p21Waf1/Cip1, and INCA1, and downregulation of cyclin D1. Moreover, depletion of CREB3L4 resulted in significantly decreased expression of a subset of androgen-receptor (AR) target genes, including PSA, FKBP5, HPGD, KLK2, and KLK4. We also demonstrated that CREB3L4 directly interacts with the AR, and increases the binding of AR to androgen response elements (AREs). We also identified a role for the unfolded protein response (and its surrogate, IRE1α), in activating CREB3L4. Cumulatively, we postulate that CREB3L4 expression is mediated by an AR-IRE1α axis, but is also directly regulated by AR-to-ARE binding. Thus, our study demonstrates that CREB3L4 plays a key role in PC cell proliferation, which is promoted by both AR and IRE1α.
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Tae-Hyun
TH
Kim
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Joo-Man
JM
Park
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Mi-Young
MY
Kim
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Yong-Ho
YH
Ahn
D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein; D015536:Down-Regulation / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D050976:Basic-Leucine Zipper Transcription Factors; C448322:CREB3L4 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D015741:Metribolone; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases