2017 Fiscal Year Annual Research Report
Identification of global epigenetic alterations indispensable for malignant transformation and mediated by the RB-ATM pathway
| Project/Area Number |
15K06834
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| Research Institution | Kanazawa University |
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Principal Investigator |
Shamma A.A.Awad 金沢大学, がん進展制御研究所, 助教 (50402839)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Keywords | RB / ATM / KAT3B / HDAC5 / Proteasome / Reprogramming proteins |
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| Outline of Annual Research Achievements |
We previously reported that RB/ATM functions control the proteasomal degradation of DNMT1 and DNA methylation silencing of tumor suppressor genes (Shamma et al. 2013). We next tried to identify global epigenetic modifications indispensable for malignant transformation of RB/ATM-deficient cells; however due to the high cost of WGBS-Seq and RNA-Seq, we focused on the UPS pathway and tried to identify important substrates targeted by the RB/ATM functions for proteasomal degradation.
Proteasomal degradation of the core reprogramming proteins determines the stem cell decision whether to proliferate or differentiate. Little is known about how the core reprogramming proteins are identified and recruited for degradation. Here, we demonstrate that mutual functions of the RB and ATM repress the pluripotency and self-renewal ability of the stem cell-like populations included in genetically modified mouse embryonic fibroblasts (MEFs) and A-T human adult fibroblasts (A-T HAFs) through acetylation-driven ubiquitination and subsequent proteasomal degradation of the core reprogramming proteins Oct3/4, Sox2, Klf4, Nanog and c-Myc (OSKNM). We discovered that RB recruits lysine acetyltransferase-3b (Kat3b) and inhibits the transcription of histone deacetylase-5 (Hdac5) whereas, ATM shuttles Hdac5 into the nucleus and serve as adaptor protein, which identify and assemble the acetylated-OSKNM proteins into ubiquitination complexes with the E3 ubiquitin ligase Uhrf1 or Fbxw7. These novel findings have important implications in regenerative medicine, neurodegenerative diseases and cancer.
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