The Long Non-Coding RNA ANRIL in Cancers

Abstract

ANRIL (Antisense Noncoding RNA in the INK4 Locus), a long non-coding RNA encoded in the human chromosome 9p21 region, is a critical factor for regulating gene expression by interacting with multiple proteins and miRNAs. It has been found to play important roles in various cellular processes, including cell cycle control and proliferation. Dysregulation of ANRIL has been associated with several diseases like cancers and cardiovascular diseases, for instance. Understanding the oncogenic role of ANRIL and its potential as a diagnostic and prognostic biomarker in cancer is crucial. This review provides insights into the regulatory mechanisms and oncogenic significance of the 9p21 locus and ANRIL in cancer.

Keywords: 9p21 locus; ANRIL; LncRNA; cancer; competitive endogenous RNA; epigenetics; gene regulation.

Figure 1

The regulatory mechanisms involving CDKN2A, CDKN2B and ARF on the cell cycle progression. In the G1 phase, the Rb protein (Retinoblastoma Protein) binds to the E2F1 transcription factor, sequestering it. Upon transitioning to the S phase, the CDK4/6 and cyclin D complex phosphorylates the Rb protein, resulting in the release of E2F1. Consequently, E2F1 becomes active and promotes the transcription of genes involved in the transition to the S phase. CDKN2A/2B inhibits the association between CDK4/6 and cyclin D, therefore acting as cyclin inhibitors to control cell cycle progression during the G1/S phase. Additionally, ARF plays a role in cell cycle modulation by promoting the dissociation of the MDM2 ubiquitin ligase from p53, leading to p53 stabilization. This stabilization activates cell cycle arrest at the G1/S barrier.

Figure 2

Representation of the different linear isoforms of ANRIL. Grey rectangles represent exons, numbered from 1 to 21. The left side displays isoform accession numbers from the Ensembl database along with alternative nomenclature ranging from 1 to 28.

Figure 3

Functions of ANRIL. ANRIL exerts various regulatory roles both in the cytoplasm and nucleus. In the cytoplasm, ANRIL (circANRIL: circular ANRIL and linANRIL: linear ANRIL) acts as a competing endogenous RNA (ceRNA) for miRNAs and proteins, thereby modulating gene expression at the post-transcriptional level. Within the nucleus, ANRIL functions as a cis-regulator, facilitating the recruitment of Polycomb group proteins (PcG) to the 9p21 locus. This leads to transcriptional repression of genes including CDKN2B, achieved through the deposition of H2AK119ub (PRC1) and H3K27me3 (PRC2) histone marks at the 9p21 locus. Furthermore, ANRIL modulates gene expression at the chromatin level in -trans by guiding the recruitment of chromatin modifiers or transcriptional activators (such as PcG, YY1…) to specific loci (e.g., NOX1, KLF2…). Emerging evidence indicates also that ANRIL impacts alternative splicing patterns. Overall, these regulatory activities predominantly enhance cell proliferation, migration, invasion, and metastasis while suppressing apoptosis and senescence, primarily attributed to the modulation of key cancer-related gene expression.