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Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling Through TRIM24 Binding Deguan Lv1,2, Feng Jia3, Yanli Hou4, Youzhou Sang2, Angel A

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Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling Through TRIM24 Binding Deguan Lv1,2, Feng Jia3, Yanli Hou4, Youzhou Sang2, Angel A Published OnlineFirst October 11, 2017; DOI: 10.1158/0008-5472.CAN-17-1388 Cancer Tumor and Stem Cell Biology Research Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding Deguan Lv1,2, Feng Jia3, Yanli Hou4, Youzhou Sang2, Angel A. Alvarez5, Weiwei Zhang2, Wei-Qiang Gao2,BoHu5, Shi-Yuan Cheng2,5, Jianwei Ge3, Yanxin Li6, and Haizhong Feng2 Abstract Lysine acetyltransferase KAT6A is a chromatin regulator that PI3K/AKT signaling and tumorigenesis. Overexpressing activated contributes to histone modification and cancer, but the basis of its AKT or PIK3CA rescued the growth inhibition due to KAT6A actions are not well understood. Here, we identify a KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogat- signaling pathway that facilitates glioblastoma (GBM), where it ed the growth-promoting effect of KAT6A. Overexpression is upregulated. KAT6A expression was associated with GBM of KAT6A or TRIM24, but not KAT6A acetyltransferase activity– patient survival. KAT6A silencing suppressed cell proliferation, deficient mutants or TRIM24 mutants lacking H3K23ac-bind- cell migration, colony formation, and tumor development in an ing sites, promoted PIK3CA expression, AKT phosphorylation, orthotopic mouse xenograft model system. Mechanistic investi- and cell proliferation. Taken together, our results define gations demonstrated that KAT6A acetylates lysine 23 of histone an essential role of KAT6A in glioma formation, rationalizing H3 (H3K23), which recruits the nuclear receptor binding protein its candidacy as a therapeutic target for GBM treatment. TRIM24 to activate PIK3CA transcription, thereby enhancing Cancer Res; 77(22); 6190–201. Ó2017 AACR. Introduction deregulated in cancer, including glioma, partially due to aberrant histone modifications and mutations (2–4). However, the Glioblastoma (GBM) is the most common primary malignant mechanisms by which histone modifiers regulate gliomagenesis cancer of the central nervous system with a grim median survival are still being elucidated. of less than 1.5 years upon diagnosis (1). Recent global genomic Lysine acetyltransferase 6A (KAT6A, also known as MYST3 and and transcriptome analyses reveal that the epigenetic landscape is MOZ) is a MYST-family histone acetyltransferase, which controls fundamental cellular processes, including gene transcription (5), cellular senescence (6), cardiac septum development (7), memory 1State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical T-cell diversity (8), and maintenance of normal hematopoietic Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, stem cells (9). Dysregulation of the KAT6A histone acetyltransfer- Shanghai Jiao Tong University, Shanghai, China. 2Renji-Med X Clinical Stem Cell 3 ase activity or aberrant expression of KAT6A has been associated Research Center, Ren Ji Hospital, Shanghai, China. Department of Neurosur- – gery, Ren Ji Hospital, Shanghai, China. 4Department of Radiotherapy, Ren Ji with oncogenesis in leukemia (10 13) and breast cancer (14). fi fi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. KAT6A's oncogenic activity was rst identi ed as a recurrent 5Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. fusion partner of the CREB binding protein (CBP) as a conse- Lurie Comprehensive Cancer Center, Northwestern University Feinberg School quence of gene translocation, t(8;16)(p11;p13) in the FAB 6 of Medicine, Chicago, Illinois. Key Laboratory of Pediatric Hematology and M4/M5 subtype of acute myeloid leukemia (AML; ref. 13). Then, Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai the KAT6A-TIF2 fusion was identified as a consequence of another Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. translocation, inv(8)(p11;p13) in AML. This AML fusion event requires the KAT6A nucleosome binding motif and TIF2-medi- Note: Supplementary data for this article are available at Cancer Research ated recruitment of CBP (10). KAT6A is composed of tandem Online (http://cancerres.aacrjournals.org/). PHD fingers, a MYST domain, an acidic region, and a Ser/Met D. Lv, F. Jia, and Y. Hou contributed equally to this article. (SM)-rich domain (15). KAT6A binds and acetylates histones via Corresponding Authors: Haizhong Feng, State Key Laboratory of Oncogenes its MYST domain (15). In addition, KAT6A and the related factor and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Lysine acetyltransferase 6B (KAT6B, also known as MORF) form a Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, tetrameric complex with ING5 (Inhibitor of growth 5), EAF6 China; Phone: 8621-6838-3921; Fax: 8621-6838-3916; E-mail: [email protected]; Yanxin Li, Pediatric Translational Medicine Institute, (Esa1-associated factor 6 ortholog), and the bromodomain-PHD fi Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong nger protein BRPF1 (15). Increasing evidence suggests that University, Shanghai 200127, China. Phone: 8621-3862-6295; E-mail: KAT6A is implicated in regulating tumor progression (16), but [email protected]; and Jianwei Ge, Department of Neurosurgery, Ren Ji mechanisms that facilitate its oncogenic activity independent of Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, gene fusion remain elusive. China. Phone: 8621-6838-3768; E-mail: [email protected] In this study, we firstly examined KAT6A expression in glioma doi: 10.1158/0008-5472.CAN-17-1388 cells and clinical GBM specimens. We then assessed the role of Ó2017 American Association for Cancer Research. KAT6A in cell proliferation, cell migration, and tumor growth in 6190 Cancer Res; 77(22) November 15, 2017 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst October 11, 2017; DOI: 10.1158/0008-5472.CAN-17-1388 KAT6A Promotes Glioma Tumorigenesis gliomas using cell culture and orthotopic xenograft models. Colony formation assay Finally, we determined the mechanisms by which KAT6A regu- Soft agar colony formation assays were performed as we lates glioma tumorigenesis. described previously (21). Briefly, 1 Â 104 cells were seeded in a 0.4% noble agar top layer with a bottom layer of 0.8% noble agar Materials and Methods in each of the triplicate wells of a 12-well plate. Cell culture media Cell lines was changed every 3 days thereafter. Colonies were scored after – LN428, LN340, U87, LN229, D54, T98G, U251, and LN444 2 3 weeks and data were analyzed. GBM cells were from ATCC, and were cultured in 10% FBS/ DMEM. All cell lines in this study were authenticated using STR shRNA knockdown and transfection DNA fingerprinting, most recently in March 2017 by Shanghai Lentiviruses were produced by cotransfecting various Biowing Applied Biotechnology Co., Ltd (Shanghai, China), and cDNA and packaging plasmids into HEK293T cells using mycoplasma infection was detected using LookOut Mycoplasma Lipofectamine 2000 reagent according to manufacturer's PCR Detection Kit (Sigma-Aldrich). Only lower passage cell lines instruction (#52758, Invitrogen). Forty-eight hours after trans- were used for the study. fection, the viral-containing supernatants were filtered and added into the culture media supplemented with 8 mg/mL polybrene. Transduced human GBM cells were harvested and Plasmids expression of exogenous proteins was validated by Western Flag-TRIM24 was a gift from Michelle Barton (University of blot analysis. Texas M.D. Anderson Cancer Center, Houston, TX; Addgene plasmid # 28138; ref. 17), pCIG-PIK3CA was a gift from Joseph RNA isolation and qRT-PCR Gleeson (Rockefeller University, New York, NY; Addgene plasmid Total RNA was isolated from cells with TRIzol Plus RNA # 73056; ref. 18), and pLNCX-Myr-AKT was a gift from Joan Purification Kit (Thermo Fisher Scientific) for reverse transcrip- Brugge (Harvard Medical School, Boston, MA; Addgene plasmid # tion with Reverse Transcription Kit (Takara) according to the 17245; ref. 19). Wild-type KAT6A cDNA was amplified from U87 manufacturer's instructions. qRT-PCR was performed with the cells, and then inserted into a pcDNA3 vector (Invitrogen). Power SYBR Green Master Mix (Life Technologies) on the Applied KAT6AG657E, KAT6AC543G/G657E, and TRIM24F979A/N980A point Biosystems StepOne Plus Real-Time Thermal Cycling Block. mutations were generated using a site-directed mutagenesis kit ÀDDC Results were analyzed using the 2 t method. Primers are listed (Invitrogen) following the manufacturer's protocol. KAT6A in Supplementary Table S1. shRNAs were purchased from Genechem, Inc. Chromatin immunoprecipitation–qPCR Immunoprecipitation and Western blotting assays Chromatin immunoprecipitation (ChIP) was performed using Cells were lysed in an immunoprecipitation (IP) buffer the Chromatin Immunoprecipitation Kit (Millipore-Upstate) (20 mmol/L Tris-HCl, pH 7.5, 150 mmol/L NaCl, 1 mmol/L according to the manufacturer's instructions. Immunoprecipi- EDTA, 2 mmol/L Na3VO4, 5 mmol/L NaF, 1%Triton X-100, and fi tated DNA was puri ed after phenol extraction and was used for protease inhibitor cocktail) at 4 C for 30 minutes. The lysates were qRT-PCR. Primers are listed in Supplementary Table S1. centrifuged, and then protein concentrations were determined. Equal amounts of cell lysates were immunoprecipitated with Tumorigenesis studies specific antibodies and protein G-agarose beads (Invitrogen). All
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