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

// Yetirajam Rajesh 1 , Angana Biswas 1 , Payel Banik 1 , Ipsita Pal 1 , Subhayan Das 1 , Sachin A. Borkar 2 , Hardik Sardana 2 , Abhijit Saha 3 , Swadesh K. Das 4 , 5 , 6 , Luni Emdad 4 , 5 , 6 , Paul B. Fisher 4 , 5 , 6 and Mahitosh Mandal 1 , 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.