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Rhabdomyosarcoma (RMS) is a deadly cancer of skeletal muscle origin. Pannexin 1 (PANX1) is down-regulated in RMS and increasing its levels drastically inhibits RMS progression. PANX1 upregulation thus represents a prospective new treatment strategy for this malignancy. However, the mechanisms regulating PANX1 expression, in RMS and other contexts, remain largely unknown. Here we show that both RMS and normal skeletal muscle express a comparable amount of  PANX1  mRNAs, but surprisingly the canonical 5′ untranslated region (5′ UTR) or 5′ leader of the transcript is completely lost in RMS. We uncover that quercetin, a natural plant flavonoid, increases PANX1 protein levels in RMS by inducing re-expression of a 5′ leader-containing  PANX1  transcript variant that is efficiently translated. This particular  PANX1  mRNA variant is also present in differentiated human skeletal muscle myoblasts (HSMM) that highly express PANX1. Mechanistically, abolishing ETV4 transcription factor binding sites in the  PANX1  promoter significantly reduced the luciferase reporter activities and  PANX1  5′ UTR levels, and both quercetin treatment in RMS cells and induction of differentiation in HSMM enriched the binding of ETV4 to its consensus element in the  PANX1  promoter. Notably, quercetin treatment promoted RMS differentiation in a PANX1-dependent manner. Further showing its therapeutic potential, quercetin treatment prevented RMS in vitro tumor formation while inducing complete regression of established spheroids. Collectively, our results demonstrate the tumor-suppressive effects of quercetin in RMS and present a hitherto undescribed mechanism of PANX1 regulation via ETV4-mediated transcription of a translationally functional 5′ leader-containing  PANX1  mRNA.

Quercetin induces pannexin 1 expression via an alternative transcript with a translationally active 5′ leader in rhabdomyosarcoma