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J Cell Physiol. 2019 Nov;234(11):21135-21144. doi: 10.1002/jcp.28716. Epub 2019 Apr 29.

Carcinogenic role of K-Ras-ERK1/2 signaling in bladder cancer via inhibition of H1.2 phosphorylation at T146.

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Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, China.


It has been reported that Ras-ERK signaling regulated tumor suppressive genes via epigenetic mechanisms. Herein, we set out to investigate the correlation between K-Ras-ERK1/2 signaling and H1.2 phosphorylation, to provide a better understanding of K-Ras-ERK signaling in cancer. A plasmid for expression of mutated K-Ras was transfected into human bladder carcinoma HT1197 cells. Western blot was carried out for testing the expression changes of ERK1/2 and H1.2. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, soft-agar colony formation assay, and transwell assay were used to test the effects of H1.2 phosphorylation at T146 (H1.2 T146ph ) on HT1197 cells growth and migration. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and chromatin immunoprecipitation (ChIP) were performed to test whether H1.2 T146ph regulated K-Ras-ERK1/2 downstream genes. Furthermore, how K-Ras-ERK1/2 regulated H1.2 T146ph expression was studied. We found that the ERK1/2 was activated when K-Ras was mutated, and H1.2 T146ph expression was significantly downregulated by K-Ras mutation. H1.2 T146E for mimicking H1.2 T146ph significantly attenuated K-Ras mutation induced increases in HT1197 cells viability, colony formation, and relative migration. Besides, H1.2 T146ph regulated the transcription of K-Ras-ERK1/2 downstream genes, including NT5E, GDF15, CARD16, CYR61, IGFBP3, and WNT16B. Furthermore, K-Ras-ERK1/2 signaling inhibited H1.2 phosphorylation at T146 through degradation of DNA-PK, and the degraded DNA-PK by K-Ras-ERK1/2 possibly via modulation of MDM2. In conclusion, the activation of K-Ras-ERK1/2 signaling will repress the phosphorylation of H1.2 at T146, and thereby, promoted the growth and migration of bladder cancer cells. K-Ras-ERK1/2 signaling repressed H1.2 phosphorylation possibly by MDM2-mediated degradation of DNA-PK.


DNA-PK; H1.2 phosphorylation; K-Ras-ERK signaling; MDM2; bladder cancer


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