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Identification of ZBTB18 as a novel colorectal tumor suppressor gene through genome-wide promoter hypermethylation analysis

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posted on 11.05.2021, 21:42 by S Bazzocco, H Dopeso, Á Martínez-Barriocanal, E Anguita, R Nieto, J Li, E García-Vidal, V Maggio, P Rodrigues, PG de Marcondes, S Schwartz, LA Aaltonen, A Sánchez, John MariadasonJohn Mariadason, D Arango
Background: Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation 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 profiling 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 significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly 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 identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly 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.

Funding

This study was partially funded by grants of the Instituto de Salud Car‑ los III and the European Regional Development Fund (ERDF; PI16/00540, PI19/00993, AC20/00022 and AC15/00066) and the Spanish Association Against Cancer (AECC GCA15152966ARAN) to Diego Arango

History

Publication Date

23/04/2021

Journal

Clinical Epigenetics

Volume

13

Issue

1

Article Number

88

Pagination

(p. 1-13)

Publisher

BioMed Central

ISSN

1868-7075

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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