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Hypoxia-induced TGF-Î2âRBFOX2âESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer by Ahuja, Neha; Ashok, Cheemala; Natua, Subhashis; Pant, Deepak; Cherian, Anna; Pandkar, Madhura R; Yadav, Pooja; Narayanan S.S., Vishnu; Mishra, Jharna; Samaiya, Atul; Shukla, Sanjeev is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## Abstract Hypoxic microenvironment heralds epithelial–mesenchymal transition (EMT), invasion and metastasis in solid tumors. Deregulation of alternative splicing (AS) of several cancer-associated genes has been instrumental in hypoxia-induced EMT. Our study in breast cancer unveils a previously unreported mechanism underlying hypoxia-mediated AS of __hMENA__, a crucial cytoskeleton remodeler during EMT. We report that the hypoxia-driven depletion of splicing regulator ESRP1 leads to skipping of __hMENA__ exon 11a producing a pro-metastatic isoform, __hMENAΔ11a__. The transcriptional repression of __ESRP1__ is mediated by SLUG, which gets stimulated via hypoxia-driven TGF-β signaling. Interestingly, RBFOX2, an otherwise RNA-binding protein, is also found to transcriptionally repress __ESRP1__ while interacting with SLUG. Similar to __SLUG__, __RBFOX2__ gets upregulated under hypoxia via TGF-β signaling. Notably, we found that the exosomal delivery of TGF-β contributes to the elevation of TGF-β signaling under hypoxia. Moreover, our results show that in addition to hMENA, hypoxia-induced TGF-β signaling contributes to global changes in AS of genes associated with EMT. Overall, our

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Author

Ahuja, Neha; Ashok, Cheemala; Natua, Subhashis; Pant, Deepak; Cherian, Anna; Pandkar, Madhura R; Yadav, Pooja; Narayanan S.S., Vishnu; Mishra, Jharna; Samaiya, Atul; Shukla, Sanjeev

Publisher

Oxford University Press (OUP) (ISSN 2632-8674)

Published

2020

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)