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Title: Identification of ZBTB18 as a novel colorectal tumor suppressor gene through genome-wide promoter hypermethylation analysis
Author: Bazzocco, Sarah
Dopeso, Higinio
Martínez-Barriocanal, Águeda
Anguita, Estefanía
Nieto, Rocío
Li, Jing
García-Vidal, Elia
Maggio, Valentina
Rodrigues, Paulo
Guimarães de Marcondes, Priscila
Schwartz Navarro, Simó
Aaltonen, Lauri A.
Sànchez, Àlex (Sànchez Pla)
Mariadason, John M.
Arango, Diego
Keywords: Càncer colorectal
Colorectal cancer
Issue Date: 23-Apr-2021
Publisher: BioMed Central
Abstract: Background: Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/ exome sequencing has signifcantly contributed to the characterization of the genetic driver alterations, further inves‑ tigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation. Results: Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a signifcant enrich‑ ment in zinc fnger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells signifcantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer. Conclusions: We identifed a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could signifcantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.
Note: Reproducció del document publicat a:
It is part of: Clinical Epigenetics, 2021, vol. 13, num. 1, p. 1-13
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ISSN: 1868-7075
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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