A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling.
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 p16INK4a. 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 p16INK4a, 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.



• 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.
Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07740, Jena, Germany.
Mohsen
M
Esmaeili
Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07740, Jena, Germany.
Thanakorn
T
Pungsrinont
Institute of Molecular Biology, University of Mainz, Mainz, Germany.|German Cancer Research Center, Heidelberg, Germany.
Andrea
A
Schaefer
Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07740, Jena, Germany. aria.baniahmad@med.uni-jena.de.
Aria
A
Baniahmad
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012669:Seminal Vesicles / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C410798:AR protein, human; C000607144:AR protein, mouse; D018398:Homeodomain Proteins; C501503:ING1 protein, human; C444654:ING2 protein, human; C512177:ING2 protein, mouse; C501505:Ing1 protein, mouse; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins
Androgen receptor; Crosstalk; ING1; ING2; Prostate; Tumor suppressor