title: Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells.
abstract: Protein arginine methyltransferase 5 (PRMT5) symmetrically methylates arginine residues of histones and non-histone protein substrates and regulates a variety of cellular processes through epigenetic control of target gene expression or post-translational modification of signaling molecules. Recent evidence suggests that PRMT5 may function as an oncogene and its overexpression contributes to the development and progression of several human cancers. However, the mechanism underlying the regulation of PRMT5 expression in cancer cells remains largely unknown. In the present study, we have mapped the proximal promoter of PRMT5 to the -240bp region and identified nuclear transcription factor Y (NF-Y) as a critical transcription factor that binds to the two inverted CCAAT boxes and regulates PRMT5 expression in multiple cancer cell lines. Further, we present evidence that loss of PRMT5 is responsible for cell growth inhibition induced by knockdown of NF-YA, a subunit of NF-Y that forms a heterotrimeric complex with NF-YB and NF-YC for function. Significantly, we have found that activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) in LNCaP prostate cancer cells down-regulates the expression of NF-YA and PRMT5 at the transcription level in a c-Fos-dependent manner. Given that down-regulation of several PKC isozymes is implicated in the development and progression of several human cancers, our findings suggest that the PKC-c-Fos-NF-Y signaling pathway may be responsible for PRMT5 overexpression in a subset of human cancer patients.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Institute of Orthopedic Diseases and Department of Orthopedics of the First Affiliated Hospital, Jinan University, Guangzhou 510630, People's Republic of China.
authors.forename: Huan-Tian
authors.initials: HT
authors.lastname: Zhang
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Dabao
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Zhen-Gang
authors.initials: ZG
authors.lastname: Zha
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address: hu1@purdue.edu.
authors.forename: Chang-Deng
authors.initials: CD
authors.lastname: Hu
mesh_terms: D023081:CCAAT-Binding Factor / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000502:physiology*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D023081:CCAAT-Binding Factor; D016760:Proto-Oncogene Proteins c-fos; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011493:Protein Kinase C
keywords: Lung cancer; NF-Y; PKC; PRMT5; Prostate cancer; c-Fos