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Ras-ERK1/2 Signaling Promotes The Development Of Osteosarcoma By Regulating H2BK12ac Through CBP

Authors Xu X, Yu H, Xu Y

Received 14 June 2019

Accepted for publication 27 August 2019

Published 24 October 2019 Volume 2019:11 Pages 9153—9163


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Chien-Feng Li

Xianlun Xu,1,2 Hao Yu,1,2 Yupeng Xu3

1Department of Traumatology, Jining No.1 People’s Hospital, Jining 272011, Shandong, People’s Republic of China; 2Affiliated Jining No.1 People’s Hospital of Jining Medical University, Jining Medical University, Jining 272067, Shandong, People’s Republic of China; 3Department of Orthopedics, Jining Bone Fracture Hospital, Jining 272000, Shandong, People’s Republic of China

Correspondence: Xianlun Xu
Department of Traumatology, Jining No.1 People’s Hospital, No. 6 Jiankang Road, Jining 272011, Shandong, People’s Republic of China
Yupeng Xu
Department of Orthopedics, Jining Bone Fracture Hospital, No. 28 Rencheng Road, Jining 272000, Shandong, People’s Republic of China
Tel +86-0537-221272

Background: H2BK12ac is an important histone acetylation pattern of H2B, which has been reported in several cancers. However, whether H2BK12ac joins in Ras-ERK1/2 activation-induced osteosarcoma (OS) cell behaviors remain unclear. The study explored this peradventure and revealed the underlying mechanism.
Methods: MG-63 cells were transfected with pEGFP-N1, pEGFP-RasWT and pEGFP-K-RasG12V/T35S, H2BK12ac and ERK1/2 expression levels were analyzed by Western blot. Effects of H2BK12ac on cell viability, migration, colony formation and cell cycle were investigated by MTT, Transwell, soft-agar colony formation and flow cytometry assays. RT-qPCR and ChIP were performed to study the effect of H2BK12ac and CBP on ERK1/2-downstream gene transcriptions.
Results: H2BK12ac was specifically down-regulated by Ras-ERK1/2 activation in MG-63 cells. Down-regulated H2BK12ac participated in regulating cell proliferation and migration of MG-63 cells, meanwhile, affected the transcription of ERK1/2-downstream genes. Additionally, silence of HDAC1 up-regulated H2BK12ac expression, and inhibited the promoting effect of Ras-ERK1/2 on MG-63 cells’ proliferation, migration and RNA expression levels of ERK1/2-downstream genes. Further, the degradation of CBP mediated by MDM2 was discovered to be linked to Ras-ERK1/2 activation-induced H2BK12ac down-regulation.
Conclusion: These findings from the study demonstrated that Ras-ERK1/2 signaling could promote the development of OS via regulating H2BK12ac through MDM2-mediated CBP degradation.

Keywords: osteosarcoma, Ras-ERK1/2 signaling, H2BK12ac, HDAC1, CBP, MDM2

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