Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Bulk RNA-Seq of Drosophila melanogaster heads after neuronal Wwox knockdown and AB42 overexpression versus control

ABSTRACT: Wwox knockdown in Drosophila melanogaster neurons (elav-GAL4) also expressing human AB42 worsens lifespan and climbing as well as increasing AB42 load. To understand these effects further we performed transcriptomics on the same genotypes. Neurons expressing RNAi Control and a LacZ control, RNAi Control and AB42, Wwox RNAi and LacZ control or Wwox RNAi and AB42. This design allowed us to pull apart the effects of knockdown, amyloid and the interaction between the two.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Hannah Clarke

PROVIDER: E-MTAB-14948 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:WWOX expression is lost during tumor progression in many human malignancies including breast cancer. To understand the effects of loss of WWOX expression we analyzed the consequences of its silencing in normal human breast cells (MCF10F). WWOX silencing led to the formation of larger cell colonies, increased cell motility and decreased cell attachment. WWOX silenced cells demonstrated deregulated expression on genes involved in cell cycle, DNA damage response and cell motility. We detected an enrichment of targets activated by the SMAD3 transcription factor. Most notably expression of ANGPTL4, FST, PTHLH and SERPINE1 were all significantly increased upon WWOX silencing. Upregulation of these genes can be reversed by re-expressing WWOX in the previously silenced cells thus suggesting an inverse correlation between WWOX protein expression and SMAD3 transcriptional activity. Importantly, we demonstrate that WWOX physically interacts with SMAD3 protein via WW domain 1, that WWOX expression dramatically decreases SMAD3 occupancy at the ANGPTL4 and SERPINE1 promoters and significantly quenches activation of a TGFβ responsive reporter (3TP-LUX). Furthermore, WWOX expression leads to intracellular redistribution of SMAD3 protein levels redirecting protein availability from the nuclear to the cytoplasmic compartment. Interestingly, meta-analysis of gene expression breast cancer datasets indicate that WWOX and ANGPTL4 expression, encoding a secreted protein of key relevance in breast cancer lung metastatic cells, are inversely correlated and the WWOXlo/ANGPTL4hi cluster of tumors are enriched in triple-negative and basal-like sub-types. In summary, we demonstrate that WWOX modulates SMAD3 signaling in breast cells via direct WW-domain binding and potential cytoplasmic sequestration of SMAD3 protein. Since loss of WWOX expression increases with breast cancer progression and it behaves as an inhibitor of SMAD3 transcriptional activity these observations may help explain, at least in part, the paradoxical pro-tumorigenic effects of TGFβ signaling in advanced breast cancer.

Dataset Information

Bulk RNA-Seq of Drosophila melanogaster heads after neuronal Wwox knockdown and AB42 overexpression versus control

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