RNA Splicing: Layered Regulation

RESEARCH HIGHLIGHTS Nature Reviews Cancer | AOP, published online 18 October 2012; doi:10.1038/nrc3388 RNA SPLICING Layered regulation Alternative splicing and epigenetic modifications, including the exchange of canonical histones for histone variants, are now widely Lara Crow/NPG accepted to contribute to the dysregulation of gene expression in (macroH2A1.1 cancer. Links between these layers and macroH2A1.2), of regulation are less clear, but a new because it has previously study has uncovered a pathway in been linked to cancer. Depletion Consistently, the authors showed which alternative splicing of histone of DDX17 and DDX5 increased that SOD3 depletion in 67NR cells variant isoforms regulates the tran- macroH2A1.1 and decreased macro- increased migration and invasion, scription of genes involved in tumour H2A1.2 levels without affecting and that adding exogenous SOD3 cell invasion. overall macroH2A1 levels in both inhibited it in 4T1 cells. SOD3 Using the 4T1 mouse model 4T1 cells and human HeLa cells. expression was higher in cells with of mammary tumour progression Furthermore, reversion to the increased macroH2A1.1 expression (a set of cell lines with a range of endogenous splicing pattern was or with lower DDX17 and DDX5 metastatic abilities when implanted induced by re-expression of DDX17 expression. Chromatin immuno- in syngeneic mice), Dardenne et al. and DDX5, and this was dependent precipitation experiments indicated first observed overexpression of the on their helicase activity. that macroH2A1.2 was incorporated DEAD box RNA helicase DDX17 in How might macroH2A1 splice in the SOD3 locus, leading to SOD3 cells that are more likely to give rise isoforms affect migration and inva- repression. to metastases (4T1 cells) compared sion? Levels of macroH2A1.2 were Similar data were obtained using with non-metastatic 67NR cells. higher in invasive cells, and this was invasive MDA-MB‑231 human DDX17 and its paralogue DDX5 required for migration and invasion. breast cancer cells. Importantly, a often have redundant functions, Conversely, macroH2A1.1 levels were low ratio of macroH2A1.1 to macro- and knocking down expression of higher in non-invasive cells, and loss H2A1.2 expression was associated either or both with small interfering of this isoform increased migration with shorter metastasis-free survival, RNAs (siRNAs) inhibited in vitro and invasion. Looking downstream, and high SOD3 expression was asso- alternative migration and invasion of 4T1 cells. the authors found that several redox ciated with longer metastasis-free splicing of DDX17 and DDX5 are known to metabolism genes, including super- survival, in a cohort of 443 patients regulate alternative splicing, and oxide dismutase 3 (SOD3), were dif- with breast cancer, indicating that histone variant the authors found that DDX17 and ferentially regulated in the presence this pathway may be relevant in isoforms DDX5 regulated the exon abun- of either macroH2A1 isoform, and by human breast tumours. regulates … dance of many genes that encode DDX17 and DDX5 depletion. SOD3 Sarah Seton-Rogers chromatin or DNA-binding factors. converts extracellular superoxide tumour cell ORIGINAL RESEARCH PAPER Dardenne, E. et al. Of these, they focused on the gene radicals into hydrogen peroxide and Splicing switch of an epigenetic regulator by RNA invasion encoding the histone variant macro inhibits cell invasion (possibly by helicases promotes tumor-cell invasiveness. H2A1 (also known as H2AFY), reducing oxidative degradation of Nature Struct. Mol. Biol. 30 Sep 2012 (doi:10.1038/ nsmb.2390) which has two splice isoforms extracellular matrix components). NATURE REVIEWS | CANCER VOLUME 12 | NOVEMBER 2012 © 2012 Macmillan Publishers Limited. All rights reserved.

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