Natural antisense transcripts in the biological hallmarks of cancer: powerful regulators hidden in the dark

Abstract

Natural antisense transcripts (NATs), which are transcribed from opposite strands of DNA with partial or complete overlap, affect multiple stages of gene expression, from epigenetic to post-translational modifications. NATs are dysregulated in various types of cancer, and an increasing number of studies focusing on NATs as pivotal regulators of the hallmarks of cancer and as promising candidates for cancer therapy are just beginning to unravel the mystery. Here, we summarize the existing knowledge on NATs to highlight their underlying mechanisms of functions in cancer biology, discuss their potential roles in therapeutic application, and explore future research directions.

Keywords: Cancer; Hallmarks of cancer; NATs; Natural antisense transcripts.

Fig. 1

NAT structural features and action models. NATs may originate from shared bidirectional promoters, independent, or latent promoters found within genes. Based on the orientation with reference to sense genes, NATs can be classified as head-to-head (5′-regions overlap), tail-to-tail (3′-regions overlap), or embedded (one transcript is completely incorporated within the other). Based on the action model, NATs can also be divided into cis-NATs and trans-NATs

Fig. 2

NATs in epigenetic modifications. aHOTAIR acts as a scaffold to tether the PRC2 and LSD1 complex and mediates H3K27 trimethylation and H3K4 demethylation. b NATs can interact, directly or indirectly, with DNA methyltransferases (DNMT3a) and guide DNA methylation, resulting in the repression of sense RNA transcription

Fig. 3

NATs in transcriptional interference. In the initiation phase: a Promoter competition, the promoters of sense and antisense genes compete for RNAP complex; b Dislodgement, the RNAP complex of the sense gene promoter is dislodged by the arrival of the antisense gene RNAP complex; c Occlusion, the promoter of the sense gene is occluded by the antisense RNAP complex during antisense transcript elongation. In the elongation phase: d Collision, RNAP complexes collide in the overlapping region of the sense and antisense genes, blocking further transcriptions; e Roadblock, the antisense gene RNAP complex blocks that of the sense gene promoter. Ps, promoter of sense gene; Pa: promoter of antisense gene

Fig. 4

NATs contribute to each of the hallmarks of cancer