title: 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.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China;; Department of Pathology, School of Basic Medicine, Central South University, 172 TongZiPo Road, Changsha, Hunan, 410013 China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China;; Department of Pathology, School of Basic Medicine, Central South University, 172 TongZiPo Road, Changsha, Hunan, 410013 China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China;; Department of Pathology, School of Basic Medicine, Central South University, 172 TongZiPo Road, Changsha, Hunan, 410013 China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Fu
authors.affiliation: Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;; Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;; Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China.
authors.forename: Chao
authors.initials: C
authors.lastname: Mao
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078 China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;; Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;; Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;; Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;; Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;; Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;; Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;; Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;; Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;; Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;; Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China.
authors.forename: Yating
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078 China;; Department of Pathology, School of Basic Medicine, Central South University, 172 TongZiPo Road, Changsha, Hunan, 410013 China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;; Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;; Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;; Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078 China;; Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, 410078 China;; Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 China.
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Tao
mesh_terms: D001254:Astrocytoma / Q000503:physiopathology*; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D013534:Survival
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D004265:DNA Helicases; C412063:HELLS protein, human
keywords: Astrocytomas; E2F1; GSK3β; Gioblastoma.; LRP6; LSH