RNAi Screening Identifies KAT8 As a Key Molecule Important for Cancer Cell Survival

Overview

Journal Int J Clin Exp Pathol

Specialty Pathology

Date 2013 May 3

PMID 23638218

Citations 10

Authors

Shuang Zhang

Xianhong Liu

Yong Zhang

Ying Cheng

Yang Li

Affiliations

Soon will be listed here.

Abstract

Histone acetyltransferases (HATs) regulate many critical cancer events, including transcriptional regulation of oncogene and tumor suppressors, chromatin structure and DNA damage response. Abnormal expression of HATs has been reported in a number of cancers. However, cellular functions of HATs in cancer and molecular mechanisms remain largely unclear. Here, we performed a lentiviral vector-mediated RNAi screen to systematically address the function of HATs in lung cancer cell growth and viability. We identified 8 HATs genes involved in A549 cell viability. Further experiments showed that KAT8 regulates G2/M cell cycle arrest through AKT/ERK-cyclin D1 signaling. Moreover, KAT8 inhibition led to p53 induction and subsequently reduced bcl-2 expression. Our results demonstrate an important role of KAT8 in cancer and suggest that KAT8 could be a novel cancer therapeutic target.

Citing Articles

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References

Muraoka M, Konishi M, Tanaka K, Shitara N, Chong J, Iwama T . p300 gene alterations in colorectal and gastric carcinomas. Oncogene. 1996; 12(7):1565-9. View

Bolden J, Peart M, Johnstone R . Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006; 5(9):769-84. DOI: 10.1038/nrd2133. View

Marmorstein R . Structure of histone acetyltransferases. J Mol Biol. 2001; 311(3):433-44. DOI: 10.1006/jmbi.2001.4859. View

Tyteca S, Legube G, Trouche D . To die or not to die: a HAT trick. Mol Cell. 2006; 24(6):807-8. DOI: 10.1016/j.molcel.2006.12.005. View

Panagopoulos I, Fioretos T, Isaksson M, Samuelsson U, Billstrom R, Strombeck B . Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Hum Mol Genet. 2001; 10(4):395-404. DOI: 10.1093/hmg/10.4.395. View

Micci F, Panagopoulos I, Bjerkehagen B, Heim S . Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma. Cancer Res. 2006; 66(1):107-12. DOI: 10.1158/0008-5472.CAN-05-2485. View

Ikura T, Ogryzko V, Grigoriev M, Groisman R, Wang J, Horikoshi M . Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell. 2000; 102(4):463-73. DOI: 10.1016/s0092-8674(00)00051-9. View

Aguiar R, Chase A, Coulthard S, MacDONALD D, Carapeti M, Reiter A . Abnormalities of chromosome band 8p11 in leukemia: two clinical syndromes can be distinguished on the basis of MOZ involvement. Blood. 1997; 90(8):3130-5. View

Iorns E, Lord C, Turner N, Ashworth A . Utilizing RNA interference to enhance cancer drug discovery. Nat Rev Drug Discov. 2007; 6(7):556-68. DOI: 10.1038/nrd2355. View

10.

Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T . p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell. 2000; 102(6):849-62. DOI: 10.1016/s0092-8674(00)00073-8. View

11.

Bulavin D, Saito S, Hollander M, Sakaguchi K, Anderson C, Appella E . Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 1999; 18(23):6845-54. PMC: 1171747. DOI: 10.1093/emboj/18.23.6845. View

12.

Luedeke M, Linnert C, Hofer M, Surowy H, Rinckleb A, Hoegel J . Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes. Cancer Epidemiol Biomarkers Prev. 2009; 18(11):3030-5. DOI: 10.1158/1055-9965.EPI-09-0772. View

13.

Minucci S, Pelicci P . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006; 6(1):38-51. DOI: 10.1038/nrc1779. View

14.

Eliseeva E, Valkov V, Jung M, Jung M . Characterization of novel inhibitors of histone acetyltransferases. Mol Cancer Ther. 2007; 6(9):2391-8. DOI: 10.1158/1535-7163.MCT-07-0159. View

15.

Di Cerbo V, Schneider R . Cancers with wrong HATs: the impact of acetylation. Brief Funct Genomics. 2013; 12(3):231-43. DOI: 10.1093/bfgp/els065. View

16.

Gayther S, Batley S, LINGER L, BANNISTER A, Thorpe K, Chin S . Mutations truncating the EP300 acetylase in human cancers. Nat Genet. 2000; 24(3):300-3. DOI: 10.1038/73536. View

17.

Pfister S, Rea S, Taipale M, Mendrzyk F, Straub B, Ittrich C . The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma. Int J Cancer. 2007; 122(6):1207-13. DOI: 10.1002/ijc.23283. View

18.

Lavoie J, LAllemain G, Brunet A, Muller R, Pouyssegur J . Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem. 1996; 271(34):20608-16. DOI: 10.1074/jbc.271.34.20608. View

19.

Levine A . p53, the cellular gatekeeper for growth and division. Cell. 1997; 88(3):323-31. DOI: 10.1016/s0092-8674(00)81871-1. View

20.

Ramljak D, Calvert R, Wiesenfeld P, Diwan B, Catipovic B, Marasas W . A potential mechanism for fumonisin B(1)-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3beta activity. Carcinogenesis. 2000; 21(8):1537-46. View