Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53-dependent senescence and favors cell transformation.

ABSTRACT: Expression of the class IIa HDACs is frequently altered in different human cancers. In mouse models these transcriptional repressors can trigger transformation, acting as bona fide oncogenes. Whether class IIa HDACs also exhibit transforming activities in human cells is currently unknown. We infected primary human fibroblasts with retroviruses to investigate the transforming activity of HDAC4 in cooperation with well-known oncogenes. We have discovered that HDAC4 triple mutant (S246A, S467A, S632A) (HDAC4-TM), a nuclear resident version of the deacetylase, triggers TP53 stabilization and OIS (oncogene-induced senescence). Unlike RAS, HDAC4-induced OIS was TP53-dependent and characterized by rapid cell cycle arrest and accumulation of an unusual pattern of γH2AX-positive foci. The inactivat

SUBMITTER: Paluvai H 

PROVIDER: S-EPMC6275271 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature