PMID- 27305909 OWN - NLM STAT- MEDLINE DCOM- 20171023 LR - 20220223 IS - 1432-1440 (Electronic) IS - 0946-2716 (Linking) VI - 94 IP - 10 DP - 2016 Oct TI - A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling. PG - 1167-1179 AB - The androgen receptor (AR) is a transcriptional factor that has a pivotal role in the development of normal and also cancerous prostate. Therefore, analyzing AR signaling is essential to understand cancerogensis and proliferation of prostate cancer (PCa). Inhibitor of growth 1 (ING1) and ING2 are tumor suppressors with reduced expression in many cancer types. There are also indications of misregulation of ING1 and ING2 in PCa. However, the roles of ING1 and ING2 in PCa and AR signaling are poorly understood. Here, we show that surprisingly the ING1b knockdown (KD) represses AR-mediated transactivation on AR key target genes in the human LNCaP PCa cells. This is associated with growth reduction of LNCaP cells by ING1 KD. In line with this, using Ing1 knockout (KO) mice, we provide further evidence that ING1 deficiency downregulates prostate-specific AR target genes in vivo. Further analyses suggest that KD of ING1b results in induction of both cellular senescence and the cell cycle inhibitor p16 (INK4a) . The unexpected finding that the ING1 KD results in growth inhibition was further analyzed and can be explained by a compensatory mechanism through enhanced levels of ING2 protein in ING1-deficient condition. Accordingly, the data suggest that ING2 interacts with AR and hampers the AR transcriptional activation, causes growth arrest, and induces cellular senescence. The data further suggest that ING2 upregulates p16 (INK4a) , which is a novel target for ING2. Taken together, our data suggest that ING2 is a novel corepressor for AR. ING2 levels are increased upon downregulation of ING1 expression indicating a compensatory mechanism and suggests a novel crosstalk between ING1 and ING2 tumor suppressors to inhibit AR signaling and induce cellular senescence in PCa cells. KEY MESSAGE: * The tumor suppressors ING1 and 2 are dysregulated in human prostate cancer. * ING1 deficiency reduces AR-mediated gene expression in vitro and in vivo. * ING2, like ING1, inhibits AR-mediated transactivation and prostate cancer cell growth. * ING1 regulates ING2. * ING1 and ING2 crosstalk with each other to inhibit AR signaling in prostate cancer. FAU - Esmaeili, Mohsen AU - Esmaeili M AD - Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07740, Jena, Germany. FAU - Pungsrinont, Thanakorn AU - Pungsrinont T AD - Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07740, Jena, Germany. FAU - Schaefer, Andrea AU - Schaefer A AD - Institute of Molecular Biology, University of Mainz, Mainz, Germany. AD - German Cancer Research Center, Heidelberg, Germany. FAU - Baniahmad, Aria AU - Baniahmad A AD - Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07740, Jena, Germany. aria.baniahmad@med.uni-jena.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160616 PL - Germany TA - J Mol Med (Berl) JT - Journal of molecular medicine (Berlin, Germany) JID - 9504370 RN - 0 (AR protein, human) RN - 0 (AR protein, mouse) RN - 0 (Homeodomain Proteins) RN - 0 (ING1 protein, human) RN - 0 (ING2 protein, human) RN - 0 (ING2 protein, mouse) RN - 0 (Ing1 protein, mouse) RN - 0 (Inhibitor of Growth Protein 1) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Receptors, Androgen) RN - 0 (Receptors, Cytoplasmic and Nuclear) RN - 0 (Tumor Suppressor Proteins) SB - IM MH - Animals MH - Cell Line, Tumor MH - Cell Movement MH - Cell Proliferation MH - Cellular Senescence MH - Homeodomain Proteins/*metabolism MH - Humans MH - Inhibitor of Growth Protein 1 MH - Intracellular Signaling Peptides and Proteins/genetics/*metabolism MH - Male MH - Mice, Knockout MH - Nuclear Proteins/genetics/*metabolism MH - Prostate/metabolism MH - Prostatic Neoplasms/metabolism MH - Receptors, Androgen/*metabolism MH - Receptors, Cytoplasmic and Nuclear/*metabolism MH - Seminal Vesicles/metabolism MH - Signal Transduction MH - Tumor Suppressor Proteins/genetics/*metabolism OTO - NOTNLM OT - Androgen receptor OT - Crosstalk OT - ING1 OT - ING2 OT - Prostate OT - Tumor suppressor EDAT- 2016/06/17 06:00 MHDA- 2017/10/24 06:00 CRDT- 2016/06/17 06:00 PHST- 2015/12/17 00:00 [received] PHST- 2016/06/10 00:00 [accepted] PHST- 2016/06/02 00:00 [revised] PHST- 2016/06/17 06:00 [pubmed] PHST- 2017/10/24 06:00 [medline] PHST- 2016/06/17 06:00 [entrez] AID - 10.1007/s00109-016-1440-1 [pii] AID - 10.1007/s00109-016-1440-1 [doi] PST - ppublish SO - J Mol Med (Berl). 2016 Oct;94(10):1167-1179. doi: 10.1007/s00109-016-1440-1. Epub 2016 Jun 16.