title: Interplay between Homeobox proteins and Polycomb repressive complexes in p16INK⁴a regulation.
abstract: The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.
authors: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, London, UK.
authors: Nadine
authors: N
authors: Martin
authors: Nikolay
authors: N
authors: Popov
authors: Francesca
authors: F
authors: Aguilo
authors: Ana
authors: A
authors: O'Loghlen
authors: Selina
authors: S
authors: Raguz
authors: Ambrosius P
authors: AP
authors: Snijders
authors: Gopuraja
authors: G
authors: Dharmalingam
authors: Side
authors: S
authors: Li
authors: Efstathia
authors: E
authors: Thymiakou
authors: Thomas
authors: T
authors: Carroll
authors: Bernd B
authors: BB
authors: Zeisig
authors: Chi Wai Eric
authors: CW
authors: So
authors: Gordon
authors: G
authors: Peters
authors: Vasso
authors: V
authors: Episkopou
authors: Martin J
authors: MJ
authors: Walsh
authors: Jesús
authors: J
authors: Gil
mesh_terms: D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C084058:HLX protein, human; D018398:Homeodomain Proteins; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1