STAT1 mediated downregulation of the tumor suppressor gene PDCD4, is driven by the atypical cadherin FAT1, in glioblastoma.

Autor: Khan MT; Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar 122052, India; Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India; Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344, USA., Almas M; Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India., Malik N; Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India; Centre for Cancer Research, National Cancer Institute, Bethesda, USA., Jalota A; Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar 122052, India; Department of Oncology, Albert Einstein College of Medicine, New York, USA., Sharma S; Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India., Ali SA; Systems Immunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Luthra K; Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India., Suri V; Neuropathalogy Laboratory, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India., Suri A; Department of Neurosurgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India., Basak S; Systems Immunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Seth P; Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar 122052, India., Chosdol K; Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India., Sinha S; Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar 122052, India; Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. Electronic address: sub_sinha@hotmail.com.
Jazyk: angličtina
Zdroj: Cellular signalling [Cell Signal] 2024 Jul; Vol. 119, pp. 111178. Date of Electronic Publication: 2024 Apr 18.
DOI: 10.1016/j.cellsig.2024.111178
Abstrakt: STAT1 (Signal Transducer and Activator of Transcription 1), belongs to the STAT protein family, essential for cytokine signaling. It has been reported to have either context dependent oncogenic or tumor suppressor roles in different tumors. Earlier, we demonstrated that Glioblastoma multiforme (GBMs) overexpressing FAT1, an atypical cadherin, had poorer outcomes. Overexpressed FAT1 promotes pro-tumorigenic inflammation, migration/invasion by downregulating tumor suppressor gene, PDCD4. Here, we demonstrate that STAT1 is a novel mediator downstream to FAT1, in downregulating PDCD4 in GBMs. In-silico analysis of GBM databases as well as q-PCR analysis in resected GBM tumors showed positive correlation between STAT1 and FAT1 mRNA levels. Kaplan-Meier analysis showed poorer survival of GBM patients having high FAT1 and STAT1 expression. SiRNA-mediated knockdown of FAT1 decreased STAT1 and increased PDCD4 expression in glioblastoma cells (LN229 and U87MG). Knockdown of STAT1 alone resulted in increased PDCD4 expression. In silico analysis of the PDCD4 promoter revealed four putative STAT1 binding sites (Site1-Site4). ChIP assay confirmed the binding of STAT1 to site1. ChIP-PCR revealed decrease in the binding of STAT1 on the PDCD4 promoter after FAT1 knockdown. Site directed mutagenesis of Site1 resulted in increased PDCD4 luciferase activity, substantiating STAT1 mediated PDCD4 inhibition. EMSA confirmed STAT1 binding to the Site 1 sequence. STAT1 knockdown led to decreased expression of pro-inflammatory cytokines and EMT markers, and reduced migration/invasion of GBM cells. This study therefore identifies STAT1 as a novel downstream mediator of FAT1, promoting pro-tumorigenic activity in GBM, by suppressing PDCD4 expression.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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