Journal
CANCER RESEARCH
Volume 77, Issue 22, Pages 6190-6201Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-1388
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Funding
- National Natural Science Foundation of China [81372704, 81572467, 81470315, 81772663, 81471855, 81372705]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [2014024]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20161310]
- New Hundred Talent Program (Outstanding Academic Leader) at Shanghai Municipal Health Bureau [2017BR021]
- Technology Transfer Project of Science & Technology Dept. at Shanghai Jiao Tong University School of Medicine [ZT201701]
- Shanghai Jiao Tong University School of Medicine Hospital Fund [14XJ10069]
- Collaborative Innovation Center for Translation Medicine at Shanghai Jiao Tong University School of Medicine [TM201502]
- Shanghai Natural Science Foundation [16ZR1420200]
- Shanghai Jiao Tong University Medical Engineering Cross Fund [YG2015QN35]
- US NIH [CA158911, NS093843, NS95634, CA209345]
- Zell Scholar Award from the Zell Family Foundation
- Northwestern Brain Tumor Institute at Northwestern University
- Brain Cancer Research Award from James S. McDonnell Foundation
- NIH/NCI training grant [T32 CA070085]
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Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac-binding sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment. (C) 2017 AACR.
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