Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is a family of soft tissue cancers that are related to the skeletal muscle lineage and predominantly occur in children and young adults. A specific chromosomal translocation t(2;13)(q35;q14) that gives rise to the chimeric oncogenic transcription factor PAX3-FOXO1 has been identified as a hallmark of the aggressive alveolar subtype of RMS. PAX3-FOXO1 cooperates with additional molecular changes to promote oncogenic transformation and tumorigenesis in various human and murine models. Its expression is generally restricted to RMS tumor cells, thus providing a very specific target for therapeutic approaches for these RMS tumors. In this article, we review the recent understanding of PAX3-FOXO1 as a transcription factor in the pathogenesis of this cancer and discuss recent developments to target this oncoprotein for treatment of RMS.

Keywords: gene fusion; oncogenic transformation; rhabdomyosarcoma; targeted therapy; transcription factor.

Figure 1

Protein domain structures of the wild-type PAX3, FOXO1 and PAX3-FOXO1 fusion proteins. The numbers indicate the corresponding amino acids present on each protein. Abbreviations: PD, Paired box domain; OP, octapeptide motif; HD, homeobox domain; P-TAD, PAX3 transactivation domain; FH, forkhead domain; KD, KIX-binding domain; F-TAD, FOXO1 transactivation domain; NLS, nuclear localization signal; NES, nuclear export signal.

Figure 2

Targetable regulations of PAX3-FOXO1 activity. GSK3β, CK2, CDK4 and PLK1 phosphorylate PAX3-FOXO1 at various serine residues. The acetyltransferase enzyme P/CAF acetylates PAX3-FOXO1 at K426/K429 lysine residues. BRD4 acts as co-transcriptional activator of PAX3-FOXO1 at its DNA target sites. The mechanism by which HDAC regulates the mRNA expression level of PAX3-FOXO1 remains unknown. These chromatin modifiers, which modulate expression of PAX3-FOXO1 target genes, can be targeted by small molecule inhibitors.