title: Tumor suppressor p16INK4A is necessary for survival of cervical carcinoma cell lines.
abstract: The tumor suppressor p16(INK4A) inhibits formation of enzymatically active complexes of cyclin-dependent kinases 4 and 6 (CDK4/6) with D-type cyclins. Oncogenic stress induces p16(INK4A) expression, which in turn triggers cellular senescence through activation of the retinoblastoma tumor suppressor. Subversion of oncogene-induced senescence is a key step during cancer development, and many tumors have lost p16(INK4A) activity by mutation or epigenetic silencing. Human papillomavirus (HPV)-associated tumors express high levels of p16(INK4A) in response to E7 oncoprotein expression. Induction of p16(INK4A) expression is not a consequence of retinoblastoma tumor suppressor inactivation but is triggered by a cellular senescence response and is mediated by epigenetic derepression through the H3K27-specific demethylase (KDM)6B. HPV E7 expression causes an acute dependence on KDM6B expression for cell survival. The p16(INK4A) tumor suppressor is a critical KDM6B downstream transcriptional target and its expression is critical for cell survival. This oncogenic p16(INK4A) activity depends on inhibition of CDK4/CDK6, suggesting that in cervical cancer cells where retinoblastoma tumor suppressor is inactivated, CDK4/CDK6 activity needs to be inhibited in order for cells to survive. Finally, we note that HPV E7 expression creates a unique cellular vulnerability to small-molecule KDM6A/B inhibitors.
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin-Drubin
authors.forename: Donglim
authors.initials: D
authors.lastname: Park
authors.forename: Karl
authors.initials: K
authors.lastname: Munger
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050725:Papillomavirus E7 Proteins; D025521:Tumor Suppressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
keywords: apoptosis; biomarker; cancer therapy; synthetic lethality
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