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

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.

KEYWORDS:

• ARNT
• RBFOX2
• alternative splicing
• lymphoid malignancies

Declaration of Interests

The authors declare no conflict of interest.

ACKNOWLEDGMENTS

This work was supported by grants from the National Institutes of Health/National Institute of Environmental Health Sciences, no. R01ES025809 (to C.W.W.) and T32ES007254 (to A.M.C.); Cancer Prevention and Research Institute of Texas no. RP190556 (to C.W.W. and M.N.K-M.); National Institutes of Health/National Heart Lung Blood Institute no. 1R01HL135031, UTMB John Sealy Memorial Endowment Pilot Award, Additional Ventures Single Ventricle Research Fund no. 4873, and American Heart Association no. 20TPA35490206 (to M.N.K-M).