Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells.
Cellular senescence is an irreversible proliferation arrest of primary cells and an important tumor suppression process. Senescence is often characterized by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which repress expression of proliferation-promoting genes. Formation of SAHF is driven by a complex of histone chaperones, HIRA and ASF1a, and depends upon prior localization of HIRA to PML nuclear bodies. However, how the SAHF assembly pathway is activated in senescent cells is not known. Here we show that expression of the canonical Wnt2 ligand and downstream canonical Wnt signals are repressed in senescent human cells. Repression of Wnt2 occurs early in senescence and independently of the pRB and p53 tumor suppressor proteins and drives relocalization of HIRA to PML bodies, formation of SAHF and senescence, likely through GSK3beta-mediated phosphorylation of HIRA. These results have major implications for our understanding of both Wnt signaling and senescence in tissue homeostasis and cancer progression.
Ye
Xiaofen
X
Department of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Zerlanko
Brad
B
Department of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Kennedy
Alyssa
A
Department of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Banumathy
Gowrishankar
G
Department of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Zhang
Rugang
R
Department of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Adams
Peter D
PD
Department of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: peter.adams@fccc.edu.
D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006570:Heterochromatin / Q000378:metabolism*; D056488:Histone Chaperones; D006801:Humans; D008024:Ligands; D018832:Molecular Chaperones; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051154:Wnt2 Protein / Q000378:metabolism
C491641:ASF1A protein, human; D018797:Cell Cycle Proteins; C086057:HIRA protein, human; D006570:Heterochromatin; D056488:Histone Chaperones; D008024:Ligands; D018832:Molecular Chaperones; D014157:Transcription Factors; C495244:WNT2 protein, human; D051153:Wnt Proteins; D051154:Wnt2 Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3