Epigenetic Disordering Drives Stemness, Senescence Escape and Tumor Heterogeneity [WGBS]

The widespread epigenome repatterning that characterizes most cancers can generate cells with diverse identities and malignant features; however, how this occurs is not known. We show that high levels of the epigenetic regulator and oncogene UHRF1 in zebrafish hepatocytes rapidly induce disordering of the DNA methylome, loss of heterochromatin, and DNA damage, resulting in cell cycle arrest, atm-tp53-mediated senescence, and acquisition of stemness.

Most cells are eliminated, but some in which UHRF1 expression is reduced transition to proliferation-competent cells, generating heterogeneous tumors comprised of cancer cells with progenitor-like features and persistently senescent cells that serve as reservoirs for new cancer cells. The gene signature from UHRF1-driven zebrafish tumors defines an immature and aggressive hepatocellular carcinoma subclass in humans. This defines epigenetic disordering, stemness, and senescence escape as requisite steps in developing aggressive and immature liver tumors.