Transcriptional regulation of HSPB1 by Friend leukemia integration-1 factor modulates radiation and temozolomide resistance in glioblastoma
Y. Rajesh, Angana Biswas, Payel Banik, Ipsita Pal, Subhayan Das, Sachin A. Borkar, Hardik Sardana, Abhijit Saha, Swadesh K. Das, Luni Emdad, Paul B. Fisher, Mahitosh Mandal
Abstract
// 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: [email protected] Paul B. Fisher, email: [email protected] 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.