The Deleted in Oral Cancer (DOC1 Aka CDK2AP1) Tumor Suppressor Gene Is Downregulated in Oral Squamous Cell Carcinoma by Multiple microRNAs

Authors

Roberto Stabile
Mario Román Cabezas
Mathijs P Verhagen
Francesco A Tucci
Thierry P P van den Bosch
Maria J De Herdt
Berdine van der Steen
Alex L Nigg
Meng Chen
Cristina Ivan
Masayoshi Shimizu
Senada Koljenović
Jose A Hardillo
C Peter Verrijzer
Robert J Baatenburg de Jong
George A Calin
Riccardo Fodde

Publication Date

5-22-2023

Journal

Cell Death & Disease

Abstract

Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1; also known as deleted in oral cancer or DOC1) is a tumor suppressor gene known to play functional roles in both cell cycle regulation and in the epigenetic control of embryonic stem cell differentiation, the latter as a core subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex. In the vast majority of oral squamous cell carcinomas (OSCC), expression of the CDK2AP1 protein is reduced or lost. Notwithstanding the latter (and the DOC1 acronym), mutations or deletions in its coding sequence are extremely rare. Accordingly, CDK2AP1 protein-deficient oral cancer cell lines express as much CDK2AP1 mRNA as proficient cell lines. Here, by combining in silico and in vitro approaches, and by taking advantage of patient-derived data and tumor material in the analysis of loss of CDK2AP1 expression, we identified a set of microRNAs, namely miR-21-5p, miR-23b-3p, miR-26b-5p, miR-93-5p, and miR-155-5p, which inhibit its translation in both cell lines and patient-derived OSCCs. Of note, no synergistic effects were observed of the different miRs on the CDK2AP1-3-UTR common target. We also developed a novel approach to the combined ISH/IF tissue microarray analysis to study the expression patterns of miRs and their target genes in the context of tumor architecture. Last, we show that CDK2AP1 loss, as the result of miRNA expression, correlates with overall survival, thus highlighting the clinical relevance of these processes for carcinomas of the oral cavity.

Keywords

Humans, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor Proteins, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, MicroRNAs, Mouth Neoplasms, Squamous Cell Carcinoma of Head and Neck, Tumor Suppressor Proteins

DOI

10.1038/s41419-023-05857-2

PMID

37217493

PMCID

PMC10202934

PubMedCentral® Posted Date

5-22-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes