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J Cell Physiol. 2019 Feb 15. doi: 10.1002/jcp.28259. [Epub ahead of print]

Ras-ERK1/2 signaling promotes the development of uveal melanoma by downregulating H3K14ac.

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Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.
Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.


Ras-extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling has been proposed as the crucial regulators in the development of various cancers. Histone acetylation at H3 lysine 14 (H3K14ac) is closely associated with gene expression and DNA damage. However, whether H3K14ac participates in mediating Ras-ERK1/2-induced cell proliferation and migration in uveal melanoma cells remains unknown. The purpose of this study is to investigate the effect of H3K14ac on Ras-ERK1/2 affected uveal melanoma cell phenotypes. MP65 cells were transfected with Ras WT and Ras G12V/T35S , the unloaded plasmid of pEGFP-N1 served as a negative control. Protein levels of phosphorylated ERK1/2 Thr202 and H3K14ac were assessed by western blot assay. Cell viability, number of colonies, migration, and the downstream genes of ERK1/2 were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2-H-tetrazolium bromide, soft-agar colony formation, transwell, and chromatin immunoprecipitation assays. HA-tag vectors of CLR3 and TIP60 and the small interfering RNAs that specific for CLR3 and MDM2 were transfected into MP65 cells to uncover the effects of CLR3, TIP60, and MDM2 on Ras-ERK1/2 mediated H3K14ac expression and MP65 cell phenotypes. We found that, Ras-ERK1/2 decreased H3K14ac expression in MP65 cells, and H3K14ac significantly suppressed Ras-ERK1/2-induced cell viability, colony formation, and migration in MP65 cells. Moreover, the transcription of CYR61, IGFBP3, WNT16B, NT5E, GDF15, and CARD16 was regulated by H3K14ac. Additionally, CLR3 silence recovered H3K14ac expression and reversed the effect of Ras-ERK1/2 on MP65 cell proliferation, migration and the mRNAs of ERK1/2 downstream genes. Besides, Ras-ERK1/2 decreased H3K14ac expression by MDM2-mediated TIP60 degradation. In conclusion, Ras-ERK1/2 promoted uveal melanoma cells growth and migration by downregulating H3K14ac via MDM2-mediated TIP60 degradation.


CLR3; ERK1/2 signaling pathway; H3K14ac; RasG12V/T35S; TIP60; uveal melanoma


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