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Title: Alternative Splicing of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Is Regulated by RBFOX2 in Lymphoid Malignancies.

Authors: Cooper, Amy M; Nutter, Curtis A; Kuyumcu-Martinez, Muge N; Wright, Casey W

Published In Mol Cell Biol, (2022 May 19)

Abstract: Aberrant alternative splicing (AS) of pre-mRNAs promotes the development and proliferation of cancerous cells. Accordingly, we had previously observed higher levels of the aryl hydrocarbon receptor nuclear translocator (ARNT) spliced variant isoform 1 in human lymphoid malignancies compared to that in normal lymphoid cells, which is a consequence of increased inclusion of alternative exon 5. ARNT is a transcription factor that has been implicated in the survival of various cancers. Notably, we found that ARNT isoform 1 promoted the growth and survival of lymphoid malignancies, but the regulatory mechanism controlling ARNT AS is unclear. Here, we report cis- and trans-regulatory elements which are important for the inclusion of ARNT exon 5. Specifically, we identified recognition motifs for the RNA-binding protein RBFOX2, which are required for RBFOX2-mediated exon 5 inclusion. RBFOX2 upregulation was observed in lymphoid malignancies, correlating with the observed increase in ARNT exon 5 inclusion. Moreover, suppression of RBFOX2 significantly reduced ARNT isoform 1 levels and cell growth. These observations reveal RBFOX2 as a critical regulator of ARNT AS in lymphoid malignancies and suggest that blocking the ARNT-specific RBFOX2 motifs to decrease ARNT isoform 1 levels is a viable option for targeting the growth of lymphoid malignancies.

PubMed ID: 35404107 Exiting the NIEHS site

MeSH Terms: Alternative Splicing/genetics; Aryl Hydrocarbon Receptor Nuclear Translocator*/genetics; Aryl Hydrocarbon Receptor Nuclear Translocator*/metabolism; Exons/genetics; Humans; Neoplasms*; Protein Isoforms/genetics; Protein Isoforms/metabolism; RNA Splicing Factors/genetics; RNA Splicing Factors/metabolism; Receptors, Aryl Hydrocarbon/metabolism; Repressor Proteins/metabolism

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