DUX4, a gene encoding a transcription factor involved in early embryogenesis, is heavily repressed in most somatic tissues while its aberrant expression is linked to facioscapulohumeral muscular dystrophy (FSHD). Recently, the deregulation of DUX4 expression was found in many cancers. While DUX4 role in FSHD is well studied, its relevance in cancer is less explored. Here we discuss multiple levels of control of DUX4 expression, including enhancer-promoter interactions, epigenetic modifications, non-coding RNAs and telomere positioning effect. We also connect disparate data on intrachromosomal contacts involving DUX4 and emphasize feedback loops in DUX4 regulation. Finally, we bridge data on DUX4 in FSHD and cancer and discuss prospective approaches for future FSHD therapies and the potential outcomes of DUX4 inhibition in cancer.

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