PRMT5 regulates alternative splicing of TCF3 under hypoxia to promote EMT and invasion in breast cancer

TL;DR

PRMT5 promotes breast cancer cell invasion under low oxygen by regulating TCF3 splicing through histone methylation.

Contribution

PRMT5's role in hypoxia-induced alternative splicing of TCF3 via histone methylation is newly established.

Findings

PRMT5 is upregulated under hypoxia via CTCF in breast cancer cells.

PRMT5 regulates TCF3 splicing through histone methylation and DNA methylation mechanisms.

The TCF3-18B isoform promotes epithelial-mesenchymal transition and cancer cell invasion.

Abstract

Tumor hypoxia induced alterations in the epigenetic landscape and alternative splicing influence cellular adaptations. PRMT5 is a type II protein arginine methyltransferase that regulates several tumorigenic events in many cancer types. However, the regulation of PRMT5 and its direct implication on aberrant alternative splicing under hypoxia remains unexplored. In this study, we observed hypoxia-induced upregulation of PRMT5 via the CTCF in human breast cancer cells. Further, PRMT5-mediated symmetric arginine dimethylation H4R3me2s and H3R8me2s directly regulated the alternative splicing of TCF3. Under hypoxia, PRMT5-mediated histone dimethylation at the intronic conserved region (ICR) present between TCF3 exon 18a and exon 18b recruits DNMT3A, resulting in DNA methylation. DNA methylation at the TCF3-ICR is recognized and bound by MeCP2 resulting in RNA-Pol II pausing, promoting the recruitment of the negative splicing factor PTBP1 to the splicing locus of TCF3 pre-mRNA. PTBP1 promotes the exclusion of exon 18a which results in the production of the pro-invasive TCF3-18B (E47) isoform which promotes EMT and invasion of breast cancer cells under hypoxia. Collectively, our results indicate PRMT5-mediated symmetric arginine dimethylation of histones regulates alternative splicing of TCF3 gene thereby enhancing EMT and invasion in breast cancer hypoxia.

PRMT5 is a histone methyltransferase upregulated in various cancer types, but its role in regulating alternative splicing events via histone methylation has not been explored. This study shows that PRMT5 regulates TCF3 alternative splicing under hypoxia and that this promotes EMT and invasion of breast cancer cells.

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