期刊
MOLECULAR CELL
卷 69, 期 6, 页码 1017-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.02.011
关键词
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资金
- NCI NIH HHS [P30 CA045508, P01 CA013106, R01 CA174793] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA045508, R01CA174793, P01CA013106] Funding Source: NIH RePORTER
The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF. We also found that MEF2C-dependent leukemias are sensitive to on-target chemical inhibition of SIK activity. This study reveals a chemical strategy to block MEF2C function in AML, highlighting how an oncogenic TF can be disabled by targeting of upstream kinases.
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