The Role of Non-Coding RNAs in Chromosomal Instability in Cancer.

Abstract

Chromosomal instability (CIN) is characterized by an increased frequency of changes in chromosome structure or number and is regarded as a hallmark of cancer. CIN plays a prevalent role in tumorigenesis and cancer progression by assisting the cancer cells' phenotypic adaptation to stress, which have been tightly linked to therapy resistance and metastasis. Both CIN-inducing and CIN-repressing agents are being clinically tested for the treatment of cancer to increase CIN levels to unsustainable levels leading to cell death or to decrease CIN levels to limit the development of drug resistance, respectively. Non-coding RNAs (ncRNAs) including microRNAs and long ncRNAs (lncRNAs) have been fundamentally implicated in CIN. The miR-22, miR-26a, miR-28, and miR-186 target important checkpoint proteins involved in mediating chromosomal stability and their expression modulation has been directly related to CIN occurrence. lncRNAs derived from telomeric, centrosomal, and enhancer regions play an important role in mediating genome stability, while specific lncRNA transcripts including genomic instability inducing RNA called Ginir, P53-responsive lncRNA termed as GUARDIN, colon cancer-associated transcript 2, PCAT2, and ncRNA activated by DNA damage called NORAD have been shown to act within CIN-associated pathways. In this review, we discuss how these ncRNAs either maintain or disrupt the stability of chromosomes and how these mechanisms could be exploited for novel therapeutic approaches targeting CIN in cancer patients. SIGNIFICANCE STATEMENT: Chromosomal instability increases tumor heterogeneity and thereby assists the phenotypic adaptation of cancer cells, causing therapy resistance and metastasis. Several microRNAs and long non-coding RNAs that have been causally linked to chromosomal instability could represent novel therapeutic targets. Understanding the role of non-coding RNAs in regulating different genes involved in driving chromosomal instability will give insights into how non-coding RNAs can be utilized toward modifying chemotherapeutic regimens in different cancers.