Lin Yu1, Jinling Xu2,3,4, Jing Liu2,3,4, Huibian Zhang1, Cuiyun Sun2,3,4, Qian Wang2,3,4, Cuijuan Shi2,3,4, Xuexia Zhou2,3,4, Dan Hua2,3,4, Wenjun Luo2,3,4, Xiuwu Bian5, Shizhu Yu2,3,4. 1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences of Tianjin Medical University, Tianjin, China. 2. Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China. 3. Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Tianjin, China. 4. Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China. 5. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Abstract
BACKGROUND: Upregulation of staphylococcal nuclease domain-containing protein 1 (SND1) is a common phenomenon in different human malignant tissues. However, little information is available on the underlying mechanisms through which SND1 affects glioma cell proliferation and invasion. METHODS: SND1, Ras homolog family member A (RhoA), and marker of proliferation Ki-67 (MKI67) were analyzed in 187 gliomas by immunostaining. The correlation between those markers and patients' prognoses was assessed using the Kaplan-Meier estimator. Gene Ontology, chromatin immunoprecipitation, electrophoretic mobility shift assay, and chromosome conformation capture were applied to identify SND1-activated target genes. We also used MTT, colony formation, transwell and orthotopic implantation assays to investigate SND1 function in glioma cell proliferative and invasive activity. RESULTS: We identified SND1 and RhoA as independent predictors of poor prognosis in glioma patients. SND1 knockdown significantly suppressed the proliferation and invasion of glioma cells. Mechanistically, we discovered that SND1 facilitated malignant glioma phenotypes by epigenetically inducing chromatin topological interaction, which activated downstream RhoA transcription. RhoA sequentially regulated expression of CCND1, CCNE1, CDK4, and CDKN1B and accelerated G1/S phase transition in glioma cell proliferation. CONCLUSIONS: Our findings identify SND1 as a novel chromatin architectural modifier and promising prognostic indicator for glioma classification and treatment.
BACKGROUND: Upregulation of staphylococcal nuclease domain-containing protein 1 (SND1) is a common phenomenon in different human malignant tissues. However, little information is available on the underlying mechanisms through which SND1 affects glioma cell proliferation and invasion. METHODS:SND1, Ras homolog family member A (RhoA), and marker of proliferation Ki-67 (MKI67) were analyzed in 187 gliomas by immunostaining. The correlation between those markers and patients' prognoses was assessed using the Kaplan-Meier estimator. Gene Ontology, chromatin immunoprecipitation, electrophoretic mobility shift assay, and chromosome conformation capture were applied to identify SND1-activated target genes. We also used MTT, colony formation, transwell and orthotopic implantation assays to investigate SND1 function in glioma cell proliferative and invasive activity. RESULTS: We identified SND1 and RhoA as independent predictors of poor prognosis in gliomapatients. SND1 knockdown significantly suppressed the proliferation and invasion of glioma cells. Mechanistically, we discovered that SND1 facilitated malignant glioma phenotypes by epigenetically inducing chromatin topological interaction, which activated downstream RhoA transcription. RhoA sequentially regulated expression of CCND1, CCNE1, CDK4, and CDKN1B and accelerated G1/S phase transition in glioma cell proliferation. CONCLUSIONS: Our findings identify SND1 as a novel chromatin architectural modifier and promising prognostic indicator for glioma classification and treatment.
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