title: Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential.
abstract: Cancer constitutes a set of diseases with heterogeneous molecular pathologies. However, there are a number of universal aberrations common to all cancers, one of these being the epigenetic silencing of tumor suppressor genes (TSGs). The silencing of TSGs is thought to be an early, driving event in the oncogenic process. With this in consideration, great efforts have been made to develop small molecules aimed at the restoration of TSGs in order to limit tumor cell proliferation and survival. However, the molecular forces that drive the broad epigenetic reprogramming and transcriptional repression of these genes remain ill-defined. Undoubtedly, understanding the molecular underpinnings of transcriptionally silenced TSGs will aid us in our ability to reactivate these key anti-cancer targets. Here, we describe what we consider to be the five most logical molecular mechanisms that may account for this widely observed phenomenon: 1) ablation of transcription factor binding, 2) overexpression of DNA methyltransferases, 3) disruption of CTCF binding, 4) elevation of EZH2 activity, 5) aberrant expression of long non-coding RNAs. The strengths and weaknesses of each proposed mechanism is highlighted, followed by an overview of clinical efforts to target these processes.
authors.affiliation: The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada. Electronic address: anna.kazanets@mail.mcgill.ca.
authors.forename: Anna
authors.initials: A
authors.lastname: Kazanets
authors.affiliation: The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada. Electronic address: tatiana.shorstova@gmail.com.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Shorstova
authors.affiliation: The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada. Electronic address: khalid.hilmi@mail.mcgill.com.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hilmi
authors.affiliation: The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada. Electronic address: maud.marques@mail.mcgill.ca.
authors.forename: Maud
authors.initials: M
authors.lastname: Marques
authors.affiliation: The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada. Electronic address: michael.witcher@mcgill.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Witcher
mesh_terms: D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000502:physiology; D022661:RNA, Untranslated / Q000502:physiology; D014158:Transcription, Genetic; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000071221:Enhancer of Zeste Homolog 2 Protein; D056572:Histone Deacetylase Inhibitors; D063151:Polycomb Repressive Complex 2; D022661:RNA, Untranslated; D000097584:DNA Methyltransferase 3B; C498409:EZH2 protein, human
keywords: CTCF; DNA methylation; Epigenetics; Histone methylation; Therapeutics; Transcriptional silencing