Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas.

Abstract

The signaling pathway-based stratification in chromatin modification could predict clinical outcome more reliably than morphology-alone-based classification schemes in gliomas. Here we reported a role of the chromatin-remodeling factor lymphoid-specific helicase (LSH) in gliomas. Among astrocytomas of grade I to III and glioblastoma of grade IV, LSH were almost completely expressed in all cases, and strongly correlated with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Ectopic expression of LSH promoted tumor formation. Up-regulation of transcription factor E2F1 in astrocytomas and glioblastoma was associated with the progression of gliomas and correlated with LSH expression. Chromatin immunoprecipitation (ChIP) analysis showed transcription factor E2F1 were recruited to the promoter region of LSH, and depletion of E2F1 decreased LSH expression and cell growth. Moreover, glycogen synthase kinase-3β (GSK-3β), an intact complex of E2F1, were also highly expressed in astrocytomas and linked with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Inhibition of GSK3β increased the enrichment of E2F1 to the LSH promoter, in turn, increased LSH expression. Lipoprotein receptor-related protein 6 (LRP6), an upstream regulator of GSK3β signaling pathway, was highly expressed in gliomas. Knockdown of LRP6 decreased LSH expression through decrease of recruitment of E2F1 to the LSH promoter leading to inhibition of cell growth. Taken together, this study reveals evidence demonstrating a mechanism by which upregulated promoted gliomas. A mechanistic link between LSH expression and activation of the LPR6/ GSK3β/E2F1 axis in gliomas illustrates a novel role of LSH in malignant astrocytomas and glioblastoma.

• Authors: Desheng Xiao, Jun Huang, Yu Pan, Hao Li, Chunyan Fu, Chao Mao, Yan Cheng, Ying Shi, Ling Chen, Yiqun Jiang, Rui Yang, Yating Liu, Jianhua Zhou, Ya Cao, Shuang Liu, Yongguang Tao
• Journal: Theranostics (Theranostics) Vol. 7 Issue 1 Pg. 132-143 ( 2017) ISSN: 1838-7640 [Electronic] Australia
• PMID: 28042322 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• E2F1 Transcription Factor
• E2F1 protein, human
• LRP6 protein, human
• Low Density Lipoprotein Receptor-Related Protein-6
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• DNA Helicases
• HELLS protein, human

Topics

• Astrocytoma (physiopathology)
• Chromatin Assembly and Disassembly
• DNA Helicases (metabolism)
• E2F1 Transcription Factor (metabolism)
• Gene Expression Regulation
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Low Density Lipoprotein Receptor-Related Protein-6 (metabolism)
• Survival