Coactivator MYST1 regulates nuclear factor-κB and androgen receptor functions during proliferation of prostate cancer cells.
In prostate cancer (PCa), the functional synergy between androgen receptor (AR) and nuclear factor-κ B (NF-κB) escalates the resistance to therapeutic regimens and promotes aggressive tumor growth. Although the underlying mechanisms are less clear, gene regulatory abilities of coactivators can bridge the transcription functions of AR and NF-κB. The present study shows that MYST1 (MOZ, YBF2 and SAS2, and TIP60 protein 1) costimulates AR and NF-κB functions in PCa cells. We demonstrate that activation of NF-κB promotes deacetylation of MYST1 by sirtuin 1. Further, the mutually exclusive interactions of MYST1 with sirtuin 1 vs AR regulate the acetylation of lysine 16 on histone H4. Notably, in AR-lacking PC3 cells and in AR-depleted LNCaP cells, diminution of MYST1 activates the cleavage of poly(ADP-ribose) polymerase and caspase 3 that leads to apoptosis. In contrast, in AR-transformed PC3 cells (PC3-AR), depletion of MYST1 induces cyclin-dependent kinase (CDK) N1A/p21, which results in G2M arrest. Concomitantly, the levels of phospho-retinoblastoma, E2F1, CDK4, and CDK6 are reduced. Finally, the expression of tumor protein D52 (TPD52) was unequivocally affected in PC3, PC3-AR, and LNCaP cells. Taken together, the results of this study reveal that the functional interactions of MYST1 with AR and NF-κB are critical for PCa progression.
Department of Structural and Chemical Biology (A.J., S.M.) and Division of Hematology and Medical Oncology (P.C.), Department of Medicine, Tisch Cancer Institute, and Division of Endocrinology (S.Y., A.C.L.), Department of Medicine, Mt. Sinai School of Medicine, New York, New York 10029; University of Rochester Medical Center School of Medicine and Dentistry (G.-Q.X.), Department of Pathology and Laboratory Medicine, Rochester, New York 14642; Department of Biology (M.P., S.M.), Medgar Evers College, Brooklyn, New York 11225; State Key Laboratory of Medical Molecular Biology (X.L., D.-P.L.), Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100005, People's Republic of China; and Department of Molecular and Cellular Pharmacology (K.L.B.), Miller School of Medicine, University of Miami, Miami, Florida 33136.
Anbalagan
A
Jaganathan
Pratima
P
Chaurasia
Guang-Qian
GQ
Xiao
Marc
M
Philizaire
Xiang
X
Lv
Shen
S
Yao
Kerry L
KL
Burnstein
De-Pei
DP
Liu
Alice C
AC
Levine
Shiraz
S
Mujtaba
D000107:Acetylation; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D059565:G2 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000502:physiology*; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D011471:Prostatic Neoplasms; D011499:Protein Processing, Post-Translational; D011944:Receptors, Androgen / Q000502:physiology*; D020218:Response Elements; D056564:Sirtuin 1 / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D016328:NF-kappa B; D011944:Receptors, Androgen; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1