KAT8 Regulates Androgen Signaling in Prostate Cancer Cells.
Androgen receptor (AR) plays pivotal roles in prostate cancer. Upon androgen stimulation, AR recruits the Protein kinase N1 (PKN1), which phosphorylates histone H3 at threonine 11, with subsequent recruitment of tryptophan, aspartic acid (WD) repeat-containing protein 5 (WDR5) and the su(var)3-9, enhancer of zeste, trithorax/mixed-lineage leukemia (SET1/MLL) histone methyltransferase complex to promote AR target gene activation and prostate cancer cell growth. However, the underlying mechanisms of target gene activation and cell growth subsequent to WDR5 recruitment are not well understood. Here, we demonstrate an epigenetic cross talk between histone modifications and AR target gene regulation. We discovered that K(lysine) acetyltransferase 8 (KAT8), a member of the MOZ, YBF2/SAS2, and TIP 60 protein 1 (MYST) family of histone acetyltransferases that catalyzes histone H4 lysine 16 acetylation, colocalized with WDR5 at AR target genes, resulting in hormone-dependent gene activation in prostate cancer cells. PKN1 or WDR5 knockdown severely inhibited KAT8 association with AR target genes and histone H4 lysine 16 acetylation upon androgen treatment. Knockdown of KAT8 significantly decreased AR target gene expression and prostate cancer cell proliferation. Collectively, these data describe a trans-histone modification pathway involving PKN1/histone H3 threonine 11 phosphorylation followed by WDR5/MLL histone methyltransferase and KAT8/histone acetyltransferase recruitment to effect androgen-dependent gene activation and prostate cancer cell proliferation.
Division of Reproductive Science in Medicine (J.-Y.K., D.C.), Department of Obstetrics and Gynecology; Division of Hematology/Oncology (J.Y.), Department of Medicine; Departments of Urology (S.A.A.), Pathology (S.A.A.), and Pharmacology (D.C.); and Robert H. Lurie Comprehensive Cancer Center (J.Y., S.A.A., D.C.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
Ji-Young
JY
Kim
Division of Reproductive Science in Medicine (J.-Y.K., D.C.), Department of Obstetrics and Gynecology; Division of Hematology/Oncology (J.Y.), Department of Medicine; Departments of Urology (S.A.A.), Pathology (S.A.A.), and Pharmacology (D.C.); and Robert H. Lurie Comprehensive Cancer Center (J.Y., S.A.A., D.C.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
Jindan
J
Yu
Division of Reproductive Science in Medicine (J.-Y.K., D.C.), Department of Obstetrics and Gynecology; Division of Hematology/Oncology (J.Y.), Department of Medicine; Departments of Urology (S.A.A.), Pathology (S.A.A.), and Pharmacology (D.C.); and Robert H. Lurie Comprehensive Cancer Center (J.Y., S.A.A., D.C.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
Sarki A
SA
Abdulkadir
Division of Reproductive Science in Medicine (J.-Y.K., D.C.), Department of Obstetrics and Gynecology; Division of Hematology/Oncology (J.Y.), Department of Medicine; Departments of Urology (S.A.A.), Pathology (S.A.A.), and Pharmacology (D.C.); and Robert H. Lurie Comprehensive Cancer Center (J.Y., S.A.A., D.C.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
Debabrata
D
Chakravarti
D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C410798:AR protein, human; D000728:Androgens; D002843:Chromatin; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; C061570:protein kinase N; D011493:Protein Kinase C