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Theranostics 2017; 7(1):132-143. doi:10.7150/thno.17032 This issue Cite

Research Paper

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

Desheng Xiao ^1,2, Jun Huang ³, Yu Pan ^1,2, Hao Li ³, Chunyan Fu ^1,2, Chao Mao^4,5,6, Yan Cheng⁷, Ying Shi^4,5,6, Ling Chen^4,5,6, Yiqun Jiang^4,5,6, Rui Yang^4,5,6, Yating Liu^4,5,6, Jianhua Zhou^1,2, Ya Cao^4,5,6, Shuang Liu⁸, Yongguang Tao^4,5,6,8✉

1. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China;
2. Department of Pathology, School of Basic Medicine, Central South University, 172 TongZiPo Road, Changsha, Hunan, 410013 China;
3. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China;
4. Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;
5. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;
6. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China;
7. Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078 China;
8. Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 China.

✉ Corresponding author: Y.T. Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Xiangya Hospital, Central South University. 87 Xiangya Road Changsha, Hunan, 410008 China Tel. +(86) 731-84805448; Fax. +(86) 731-84470589; Email: taoyongedu.cn. More

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.

Keywords: LSH, LRP6, E2F1, GSK3β, Astrocytomas, Gioblastoma.

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