Temozolomide treatment induces lncRNA MALAT1 in an NF-κB and p53 codependent manner in Glioblastoma

David J. Voce, Giovanna M. Bernal, Longtao Wu, Clayton D. Crawley, Wei Zhang, Nassir M. Mansour, Kirk E. Cahill, Szymon J. Szymura, Abhineet Uppal, David R. Raleigh, Ruben Spretz, Luis Nunez, Gustavo Larsen, Nikolai N. Khodarev, Ralph R. Weichselbaum, Bakhtiar Yamini

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Alkylating chemotherapy is a central component of the management of glioblastoma (GBM). Among the factors that regulate the response to alkylation damage, NF-κB acts to both promote and block cytotoxicity. In this study, we used genome-wide expression analysis in U87 GBM to identify NF-κB-dependent factors altered in response to temozolomide and found the long noncoding RNA (lncRNA) MALAT1 as one of the most significantly upregulated. In addition, we demonstrated that MALAT1 expression was coregulated by p50 (p105) and p53 via novel kB- and p53-binding sites in the proximal MALAT1 coding region. Temozolomide treatment inhibited p50 recruitment to its cognate element as a function of Ser329 phosphorylation while concomitantly increasing p53 recruitment. Moreover, luciferase reporter studies demonstrated that both kB and p53 cis-elements were required for efficient transactivation in response to temozolomide. Depletion of MALAT1 sensitized patient-derived GBM cells to temozolomide cytotoxicity, and in vivo delivery of nanoparticleencapsulated anti-MALAT1 siRNA increased the efficacy of temozolomide in mice bearing intracranial GBM xenografts. Despite these observations, in situ hybridization of GBM specimens and analysis of publicly available datasets revealed that MALAT1 expression within GBM tissue was not prognostic of overall survival. Together, these findings support MALAT1 as a target for chemosensitization of GBM and identify p50 and p52 as primary regulators of this ncRNA. Significance: These findings identify NF-κB and p53 as regulators of the lncRNA MALAT1 and suggest MALAT1 as a potential target for the chemosensitization of GBM.

Original languageEnglish (US)
Pages (from-to)2536-2548
Number of pages13
JournalCancer Research
Volume79
Issue number10
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Temozolomide treatment induces lncRNA MALAT1 in an NF-κB and p53 codependent manner in Glioblastoma'. Together they form a unique fingerprint.

  • Cite this

    Voce, D. J., Bernal, G. M., Wu, L., Crawley, C. D., Zhang, W., Mansour, N. M., Cahill, K. E., Szymura, S. J., Uppal, A., Raleigh, D. R., Spretz, R., Nunez, L., Larsen, G., Khodarev, N. N., Weichselbaum, R. R., & Yamini, B. (2019). Temozolomide treatment induces lncRNA MALAT1 in an NF-κB and p53 codependent manner in Glioblastoma. Cancer Research, 79(10), 2536-2548. https://doi.org/10.1158/0008-5472.CAN-18-2170