Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene Review Drug-induced modifications and modulations of microRNAs and long non- coding RNAs for future therapy against Glioblastoma Multiforme M. Janaki Ramaiah a, ⁎ , Karthikeyan Divyapriya a , Sarwareddy Kartik Kumar a , Y.B.R.D. Rajesh b a Laboratory of Functional Genomics and Disease Biology, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, Tamil Nadu, India b Organic Synthesis and Catalysis Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, Tamil Nadu, India ARTICLE INFO Keywords: MicroRNAs Long non-coding RNAs Circular RNAs Glioblastoma Multiforme HDAC inhibitors Suberoylanilidehydroxamic acid Temozolomide Bromo- and Extra-terminal O6-methylguanine methyltransferase HOX transcript antisense RNA 3′-UTR GBM therapy ABSTRACT Non-coding RNAs are known to participate in cancer initiation, progression, and metastasis by regulating the status of chromatin epigenetics and gene expression. Although these non-coding RNAs do not possess defined protein-coding potential, they are involved in the expression and stability of messenger RNA (mRNA). The length of microRNAs (miRs) ranges between 20 and 22 nt, whereas, long non-coding RNAs (lncRNAs) length ranges between 200 nt to 1 Kb. In the case of circular RNAs (circRNAs), the size varies depending upon the length of the exon from where they were derived. Epigenetic regulations of miR and lncRNA genes will influence the gene expression by modulating histone acetylation and methylation patterns. Especially, lncRNAs will act as a scaffold for various epigenetic proteins, such as EZH2 and LSD1, and influence the chromatin epigenetic state at various genomic loci involved at silencing. Thus investigations on the expression of lncRNAs and designing drugs to modulate the expression of these genes will have a profound impact on future therapeutics against cancers such as Glioblastoma Multiforme (GBM) and also against various other diseases. With the recent advancements in genome-wide transcriptomic studies, scientists are focused on the non-coding RNAs and their regulations on various cellular processes involved in GBM and on other types of cancer as well as trying to understand possible epigenetic modulations that help in generating promising therapeutics for the future generations. In this review, the involvement of epigenetic proteins, enzymes that change chromatin architecture and epigenetic landscape and new roles of lncRNAs that are involved in GBM progression are elaborately discussed. 1. Introduction Glioblastoma Multiforme (GBM) is a rapidly proliferating brain cancer type characterized by high invasion and resistance to apoptosis. GBM patients will survive up to 10–14 months (Omuro and DeAngelis, 2013). In general, the Gliomas are classified into four different types which include oligodendrogliomas, astrocytomas, Oligoastrocytomas and ependymomas (Louis et al., 2007). The GBM type (IV) is found to have high malignancy and survival period is about one year (Wen and Kesari, 2008). Several studies have indicated epigenetic aberrations as a key driver of cancer (Falkenberg and Johnstone, 2014). Thus in- vestigations on chromatin epigenetic status might provide valuable information about the initiation and progression of GBM and may fa- cilitate the advancement of disease diagnosis and drug discovery. 2. HDAC inhibitors and GBM cancer Recent studies have identified epigenetic modulators as future therapeutic agents against GBM. Also, it was evident from the studies that epigenetic modifying drugs such as HDAC inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) can reverse the epigenetic state of various genes that are highly expressed in cancer cells and thus help in mesenchymal to epithelial transition (MET). Studies have identified that epigenetic mechanisms and modifica- tions are tightly associated with cancer progression and therapy re- sistance (Taby and Issa, 2010). Many studies found that histone acet- yltransferases (HATs) and histone deacetylase (HDAC) enzymes dictate the epigenetic status of cancer cell that will influence the gene ex- pression and non-coding RNA expression in cancer cells (Yang and Seto, https://doi.org/10.1016/j.gene.2019.144126 Received 4 April 2019; Received in revised form 11 September 2019; Accepted 12 September 2019 Abbreviations: miRs, MicroRNAs; lncRNAs, Long non-coding RNAs; circRNAs, Circular RNAs; GBM, Glioblastoma Multiforme; HDACi, HDAC inhibitors; SAHA, Suberoylanilidehydroxamic acid; TMZ, Temozolomide; BET, Bromo- and Extra-terminal; MGMT, O6-methylguanine methyltransferase; HOTAIR, HOX transcript antisense RNA ⁎ Corresponding author. E-mail address: janakiramaiah@scbt.sastra.edu (M. Janaki Ramaiah). Gene 723 (2020) 144126 Available online 04 October 2019 0378-1119/ © 2019 Elsevier B.V. All rights reserved. T