Molecular Mechanisms of lncRNAs in the Dependent Regulation of Cancer and Their Potential Therapeutic Use

Abstract

Deep whole genome and transcriptome sequencing have highlighted the importance of an emerging class of non-coding RNA longer than 200 nucleotides (i.e., long non-coding RNAs (lncRNAs)) that are involved in multiple cellular processes such as cell differentiation, embryonic development, and tissue homeostasis. Cancer is a prime example derived from a loss of homeostasis, primarily caused by genetic alterations both in the genomic and epigenetic landscape, which results in deregulation of the gene networks. Deregulation of the expression of many lncRNAs in samples, tissues or patients has been pointed out as a molecular regulator in carcinogenesis, with them acting as oncogenes or tumor suppressor genes. Herein, we summarize the distinct molecular regulatory mechanisms described in literature in which lncRNAs modulate carcinogenesis, emphasizing epigenetic and genetic alterations in particular. Furthermore, we also reviewed the current strategies used to block lncRNA oncogenic functions and their usefulness as potential therapeutic targets in several carcinomas.

Keywords: cancer disease; lncRNAs; therapeutic drugs.

Figure 1

Representative scheme of the main human carcinomas and related lncRNAs. Note that the red lncRNAs act as oncogenes, while the green lncRNAs act as tumor suppressor genes.

Figure 2

Epigenetic mechanism involved in carcinogenesis. (A) Histone methylation exerted by HOTAIR-PRC2 complex to repress expression of several genes such as Hoxd10, PGR, PCDH, or Jam2 with a protective role against metastasis in breast cancer cell line. (B) TCF21 promoter demethylation exerted by TARID1-GADD45A, which positively modulates expression of the TCF21 gene, a protective factor against head and neck squamous cell carcinoma (HNSCC). (C) Ubiquitination of EZH2, a subunit of PRC2, by ANCR reducing negative marks at Hoxd10 or E-Cadherin genes, exerting a protective role against EMT and metastasis in breast cancer cell line. (D) Required binding SPKQ-Neat1 for the formation of paraspeckles. Downregulation of Neat1 is translated in the high availability of SPKQ and therein the upregulation of apoptosis genes such as BLC2 or BAX.

Figure 3

Main regulatory mechanisms of lncRNAs at the post-transcriptional level. (A) Competing sponge lncRNAs act to form an lncRNA-miRNA complex, avoiding the degradation of 3′UTR target genes, therein repressing the translation of them. (B) lncRNAs binding mRNA targets and avoiding the ribosome-initiated translation process. In sharp contrast, the mRNA-lncRNA complex attenuates the binding of repressed protein translation. (C) lncRNAs can act as positive modulators of rRNA synthesis, increasing the ribosome pool necessary for the increased protein demand in cancer cells. (D) lncRNAs can modulate the splicing process, leading to transcription of different isoforms that exert pivotal roles in several carcinomas.