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Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer.

ABSTRACT: Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic re-programming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease. The impressive number of hypoxia-induced alternative spliced protein isoforms that characterize tumour progression, classifies hypoxia-induced alternative splicing as the 11th hallmark of cancer, and offers a fertile source of potential diagnostic/prognostic markers and therapeutic targets.

SUBMITTER: Farina AR

PROVIDER: S-EPMC7294618 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer.

Farina Antonietta Rosella AR Cappabianca Lucia L Sebastiano Michela M Zelli Veronica V Guadagni Stefano S Mackay Andrew Reay AR

Journal of experimental & clinical cancer research : CR 20200615 1

Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative sp ...[more]

PMID: 32536347

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Project description:BackgroundAdaptation to low oxygen by changing gene expression is vitally important for cell survival and tissue development. The sprouting of new blood vessels, initiated from endothelial cells, restores the oxygen supply of ischemic tissues. In contrast to the transcriptional response induced by hypoxia, which is mainly mediated by members of the HIF family, there are only few studies investigating alternative splicing events. Therefore, we performed an exon array for the genome-wide analysis of hypoxia-related changes of alternative splicing in endothelial cells.Methodology/principal findingsHuman umbilical vein endothelial cells (HUVECs) were incubated under hypoxic conditions (1% O(2)) for 48 h. Genome-wide transcript and exon expression levels were assessed using the Affymetrix GeneChip Human Exon 1.0 ST Array. We found altered expression of 294 genes after hypoxia treatment. Upregulated genes are highly enriched in glucose metabolism and angiogenesis related processes, whereas downregulated genes are mainly connected to cell cycle and DNA repair. Thus, gene expression patterns recapitulate known adaptations to low oxygen supply. Alternative splicing events, until now not related to hypoxia, are shown for nine genes: six which are implicated in angiogenesis-mediated cytoskeleton remodeling (cask, itsn1, larp6, sptan1, tpm1 and robo1); one, which is involved in the synthesis of membrane-anchors (pign) and two universal regulators of gene expression (cugbp1 and max).Conclusions/significanceFor the first time, this study investigates changes in splicing in the physiological response to hypoxia on a genome-wide scale. Nine alternative splicing events, until now not related to hypoxia, are reported, considerably expanding the information on splicing changes due to low oxygen supply. Therefore, this study provides further knowledge on hypoxia induced gene expression changes and presents new starting points to study the hypoxia adaptation of endothelial cells.

Project description:The tumor microenvironment is marked by gradients in the level of oxygen and nutrients, with oxygen levels reaching a minimum at the core of the tumor, a condition known as tumor hypoxia. Mediated by members of the HIF family of transcription factors, hypoxia leads to a more aggressive tumor phenotype by transactivation of several genes as well as reprogramming of pre-mRNA splicing. Intragenic DNA methylation, which is known to affect alternative splicing in cancer, could be one of several reasons behind the changes in splicing patterns under hypoxia. Here, we have tried to establish a correlation between intragenicDNA methylation and alternative usage of exons in tumor hypoxia. First, we have generated a customhypoxia signature consisting of 34 genes that are upregulated under hypoxia and are direct targets of HIF-1α. Using this gene expression signature, we have successfully stratified publicly available breast cancer patient samples into hypoxia positive and hypoxia negative groups followed by mining of differentially spliced isoforms between these groups. The Hypoxia Hallmark signature from MSigDB was also used independently to stratify the same tumor samples into hypoxic and normoxic.We found that 821 genes were showing differential splicing between samples stratified using a custom signature, whereas, 911 genes were showing differential splicing between samples stratified using the MSigDB signature. Finally, we performed multiple correlation tests between the methylation levels (β) of microarray probes located within 1 kilo base pairs of isoform-specific exons using those exons' expression levels in the same patient samples in which the methylation level was recorded. We found that the expression level of one of the exons ofDHX32 and BICD2 significantly correlated with the methylation levels, and we were also able to predict patient survival (p-value: 0.02 for DHX32 and 0.0024 for BICD2). Our findings provide new insights into the potential functional role of intragenic DNA methylation in modulating alternative splicing during hypoxia.

Project description:Jasmonate is an essential phytohormone regulating plant growth, development, and defense. Alternative splicing (AS) in jasmonate ZIM-domain (JAZ) repressors is well-characterized and plays an important role in jasmonate signaling regulation. However, it is unknown whether other genes in the jasmonate signaling pathway are regulated by AS. We explore the potential for AS regulation in three Arabidopsis genotypes (WT, jaz2, jaz7) in response to methyl jasmonate (MeJA) treatment with respect to: (a) differential AS, (b) differential miRNA targeted AS, and (c) AS isoforms with novel functions. AS events identified from transcriptomic data were validated with proteomic data. Protein interaction networks identified two genes, SKIP and ALY4 whose products have both DNA- and RNA-binding affinities, as potential key regulators mediating jasmonate signaling and AS regulation. We observed cases where AS alone, or AS and transcriptional regulation together, can influence gene expression in response to MeJA. Twenty-one genes contain predicted miRNA target sites subjected to AS, which implies that AS is coupled to miRNA regulation. We identified 30 cases where alternatively spliced isoforms may have novel functions. For example, AS of bHLH160 generates an isoform without a basic domain, which may convert it from an activator to a repressor. Our study identified potential key regulators in AS regulation of jasmonate signaling pathway. These findings highlight the importance of AS regulation in the jasmonate signaling pathway, both alone and in collaboration with other regulators. Significance statement:By exploring alternative splicing, we demonstrate its regulation in the jasmonate signaling pathway alone or in collaboration with other posttranscriptional regulations such as nonsense and microRNA-mediated decay. A signal transduction network model for alternative splicing in jasmonate signaling pathway was generated, contributing to our understanding for this important, prevalent, but relatively unexplored regulatory mechanism in plants.

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Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer.

Publications

Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer.

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