Oncotarget

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Transcriptional regulation of HSPB1 by Friend leukemia integration-1 factor modulates radiation and temozolomide resistance in glioblastoma

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Oncotarget. 2020; 11:1097-1108. https://doi.org/10.18632/oncotarget.27425

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Yetirajam Rajesh, Angana Biswas, Payel Banik, Ipsita Pal, Subhayan Das, Sachin A. Borkar, Hardik Sardana, Abhijit Saha, Swadesh K. Das, Luni Emdad, Paul B. Fisher _ and Mahitosh Mandal _

Abstract

Yetirajam Rajesh1, Angana Biswas1, Payel Banik1, Ipsita Pal1, Subhayan Das1, Sachin A. Borkar2, Hardik Sardana2, Abhijit Saha3, Swadesh K. Das4,5,6, Luni Emdad4,5,6, Paul B. Fisher4,5,6 and Mahitosh Mandal1,4,5

1 School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India

2 Department of Neurosurgery & Gamma Knife, All India Institute of Medical Sciences, New Delhi, India

3 Radiation Department, UGC DAE Consortium, Jadavpur University, Kolkata, India

4 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

5 VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

6 VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

Correspondence to:

Mahitosh Mandal,email: mahitosh@smst.iitkgp.ac.in
Paul B. Fisher,email: paul.fisher@vcuhealth.org

Keywords: HSPB1; RNAseq; Fli-1; radioresistant GBM; temozolomide resistant GBM

Received: November 11, 2019     Accepted: December 21, 2019     Published: March 31, 2020

ABSTRACT

Glioblastoma (GBM) is the most common primary brain tumor and is invariably fatal. Heat shock proteins (HSPs) provide protein signatures/biomarkers for GBM that afford potential as targets for developing anti-GBM drugs. In GBM, elevated expression of hypoxia inducible factors under the influence of Ets family proteins significantly promotes the expression of HSPs. RNAseq analysis identified HSPB1 as a prominent upregulated HSP in GBM and in radiation resistant/temozolomide resistant (radio/TMZR) GBM. Here, we established friend leukemia integration 1 (Fli-1), a member of Ets family to be playing a transcriptional regulatory role on the HSPB1 gene. Fli-1 binds to nucleotide residues GGAA at binding sites 3, 6 and 7 in the 5-kb upstream region of HSPB1. Fli-1 has been linked to oncogenic transformation with upregulation in radio/TMZR GBM. Overexpression of Fli-1 in GBM promotes resistance, whereas Fli-1 knockdown in radio/TMZR GBM cells suppresses resistance. We identify the underlying molecular mechanisms of Fli-1-mediated regulation of HSPB1 that drive extracellular matrix remodeling and epithelial to mesenchymal transition in radio/TMZR GBM cells. This study uncovers Fli-1 as a potential therapeutic target for combating radiation and temozolomide resistance in GBM.


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