DUX4 expression in cancer induces a metastable early embryonic totipotent program
Andrew A. Smith,
Yee Nip,
Sean R. Bennett,
Danielle C. Hamm,
Richard J.L.F. Lemmers,
Patrick J. van der Vliet,
Manu Setty,
Silvère M. van der Maarel,
Stephen J. Tapscott
Affiliations
Andrew A. Smith
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA
Yee Nip
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Sean R. Bennett
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Danielle C. Hamm
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Richard J.L.F. Lemmers
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Patrick J. van der Vliet
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Manu Setty
Basic Sciences Division and Translational Science IRC, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Silvère M. van der Maarel
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Stephen J. Tapscott
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Neurology, University of Washington, Seattle WA 98105, USA; Corresponding author
Summary: The transcription factor DUX4 regulates a portion of the zygotic gene activation (ZGA) program in the early embryo. Many cancers express DUX4 but it is unknown whether this generates cells similar to early embryonic stem cells. Here we identified cancer cell lines that express DUX4 and showed that DUX4 is transiently expressed in a small subset of the cells. DUX4 expression activates the DUX4-regulated ZGA transcriptional program, the subsequent 8C-like program, and markers of early embryonic lineages, while suppressing steady-state and interferon-induced MHC class I expression. Although DUX4 was expressed in a small number of cells under standard culture conditions, DNA damage or changes in growth conditions increased the fraction of cells expressing DUX4 and its downstream programs. Our demonstration that transient expression of endogenous DUX4 in cancer cells induces a metastable early embryonic stem cell program and suppresses antigen presentation has implications for cancer growth, progression, and immune evasion.
