KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma.

Autor: Sobral LM; Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA., Hicks HM; Cancer Biology Graduate Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA., Parrish JK; Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA., McCann TS; Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA., Hsieh J; Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.; Cancer Biology Graduate Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.; Medical Scientist Training Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA., Goodspeed A; Department of Pharmacology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.; Bioinformatics Shared Resource, University of Colorado Cancer Center, Aurora, CO, USA., Costello JC; Department of Pharmacology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.; Bioinformatics Shared Resource, University of Colorado Cancer Center, Aurora, CO, USA., Black JC; Department of Pharmacology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA., Jedlicka P; Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.; Cancer Biology Graduate Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.; Medical Scientist Training Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2020 Oct; Vol. 14 (10), pp. 2471-2486. Date of Electronic Publication: 2020 Aug 05.
DOI: 10.1002/1878-0261.12769
Abstrakt: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young adults. RMS exists as two major disease subtypes, oncofusion-negative RMS (FN-RMS) and oncofusion-positive RMS (FP-RMS). FP-RMS is characterized by recurrent PAX3/7-FOXO1 driver oncofusions and is a biologically and clinically aggressive disease. Recent studies have revealed FP-RMS to have a strong epigenetic basis. Epigenetic mechanisms represent potential new therapeutic vulnerabilities in FP-RMS, but their complex details remain to be defined. We previously identified a new disease-promoting epigenetic axis in RMS, involving the chromatin factor KDM3A and the Ets1 transcription factor. In the present study, we define the KDM3A and Ets1 FP-RMS transcriptomes and show that these interface with the recently characterized PAX3/FOXO1-driven gene expression program. KDM3A and Ets1 positively control numerous known and candidate novel PAX3/FOXO1-induced RMS-promoting genes, including subsets under control of PAX3/FOXO1-associated superenhancers (SE), such as MEST. Interestingly, KDM3A and Ets1 also positively control a number of known and candidate novel FP-RMS-promoting, but not PAX3/FOXO1-dependent, genes. Epistatically, Ets1 is downstream of, and exerts disease-promoting effects similar to, both KDM3A and PAX3/FOXO1. MEST also manifests disease-promoting properties in FP-RMS, and KDM3A and Ets1 each impacts activation of the PAX3/FOXO1-associated MEST SE. Taken together, our studies show that the KDM3A/Ets1 epigenetic axis plays an important role in disease promotion in FP-RMS, and provide insight into potential new ways to target aggressive phenotypes in this disease.
(© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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