lncRNAs – an Emerging Powerhouse in the Battle between Life and Death of Tumor Cells

Long non-coding RNAs (lncRNAs) represent a class of non-protein coding transcripts longer than 200 nucleotides that have aptitude for regulating gene expression at the transcriptional, post-transcriptional or epigenetic levels. In recent years, lncRNAs, which are believed to be the largest transcript class in the transcriptomes, have emerged as important players in a variety of biological processes. Notably, the identification and characterization of numerous lncRNAs in the past decade has revealed a role for these molecules in the regulation of cancer cell survival and death. It is likely that this class of non-coding RNA constitutes a critical contributor to the assorted known or/and unknown mechanisms of intrinsic or acquired drug resistance. Moreover, the expression of lncRNAs is altered in various patho-physiological conditions, including cancer. Therefore, lncRNAs represent potentially important targets in predicting or altering the sensitivity or resistance of cancer cells to various therapies. Here, the authors provide an overview on the molecular functions of lncRNAs, and discuss their impact and importance in cancer development, progression, and therapeutic outcome. They also provide a perspective on how lncRNAs may alter the efficacy of cancer therapy and the promise of lncRNAs as novel therapeutic targets for overcoming chemoresistance. A better understanding of the functional roles of lncRNA in cancer can ultimately translate to the development of novel, lncRNA-based intervention strategies for the treatment or prevention of drug-resistant cancer.

Multiple mechanisms of lncRNA in regulating gene expression

(A) lncRNAs can function as modulators of epigenetics by recruiting one or more chromatin modifying proteins to specific genomic loci and inducing chromatin modifications (e.g., DNA methylation, histone modification, chromatin remodeling). A1, The nascent ANRIL lncRNA is transcribed by RNA polymerase II in the INK4b-ARF-INK4a gene cluster. Both PRC1 and PRC2 can interact with ANRIL to form heterochromatin surrounding the locus, leading to its repression in cis. A2, HOTAIR is a trans-acting regulator of the HOXD genes. The 5′ domain of HOTAIR binds to PRC2, whereas the 3′ terminus of HOTAIR binds to the LSD1/CoREST/REST complex, which coordinates histone H3 lysine 27 methylation and lysine 4 demethylation at the HOXD locus in trans. (B) lncRNAs can regulate gene transcription via recruiting specific transcription-associated factors to their target gene promoters. Depending on the nature of these transcription-associated factors, the expression of target gene is activated or repressed. (C) lncRNAs-mediated post-transcriptional regulation: C1, antisense lncRNA can bind to the sense pre-mRNA, and the resultant RNA:RNA duplex can recruit ADAR enzymes, which catalyze adenosine to inosine conversion; C2, lncRNAs regulate alternative splicing of pre-mRNAs by interacting with the spliceosomal machinery; C3, lncRNAs can be processed into small, single- or double-stranded RNAs that may act as endo-siRNAs or miRNAs, which subsequently control target gene expression; C4, lncRNAs can act as a “miRNA sponge” to sequester miRNAs and relieve miRNA-mediated repression of target mRNA.