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.
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).