Smarcd1 Inhibits the Malignant Phenotypes of Human Glioblastoma Cells via Crosstalk with Notch1

• Published in: Molecular neurobiology Vol. 58; no. 4; pp. 1438 - 1452
• Main Authors: Zhu, Yihao, Wang, Handong, Fei, Maoxing, Tang, Ting, Niu, Wenhao, Zhang, Li
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-04-2021; Springer Nature B.V
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Biology; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cell viability; Chemoresistance; Cholecystokinin; Chromatin remodeling; Chromosomal Proteins, Non-Histone - metabolism; DNA biosynthesis; DNA repair; Down-Regulation - drug effects; Down-Regulation - genetics; Evolutionary conservation; Flow cytometry; G1 Phase - drug effects; G1 Phase - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene regulation; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Glioma; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neurobiology; Neurology; Neurosciences; Notch1 protein; Phenotype; Phenotypes; Receptor, Notch1 - metabolism; Recombination; Signal Transduction - drug effects; Statistical analysis; SWI/SNF complex; Temozolomide - pharmacology; Transcription Factor HES-1 - genetics; Transcription Factor HES-1 - metabolism; Transcription, Genetic - drug effects; Tumor Suppressor Protein p53 - metabolism; Tumorigenicity; Notch1 signaling pathway; Proliferation; Smarcd1; Migration; Glioblastoma; Chemoresistance
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-020-02190-z

Smarcd1 is a component of an evolutionary conserved chromatin remodeling complex—SWI/SNF, which is involved in transcription factor recruitment, DNA replication, recombination, and repair. Suppression of the SWI/SNF complex required for cellular differentiation and gene regulation may be inducible for cell proliferation and tumorigenicity. However, the inhibitory role of Smarcd1 in human glioblastoma cells has not been well illustrated. Both U87 and U251 human glioblastoma cell lines were employed in the present study. The lentivirus-mediated gene knockdown and overexpression approach was conducted to determine the function of Smarcd1. The protein levels were tested by western blot, and the relative mRNA contents were detected by quantitative real-time PCR. Cell viability was tested by CCK-8 and colony-forming assay. Transwell assays were utilized to evaluate the motility and invasive ability. Flow cytometry was employed to analyze cell cycle and apoptosis. SPSS software was used for statistical analysis. Low expression of Smarcd1 was observed in glioblastoma cell lines and in patients with high-grade glioma. Importantly, the depletion of Smarcd1 promoted cell proliferation, invasion, and chemoresistance, whereas enhanced expression of Smarcd1 inhibited tumor-malignant phenotypes. Mechanistic research demonstrated that overexpression of Smarcd1 decreased the expression of Notch1, while knockdown of Notch1 increased the expression of Smarcd1 through Hes1 suppression. Hence, the crosstalk between Smarcd1 and Notch1, which formed a feedback loop, was crucial in regulation of glioblastoma malignant phenotypes. Furthermore, targeting Smarcd1 could be a potential strategy for human glioblastoma treatment.