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

Molecular Oncology
Lays Martin SobralP Jedlicka

Abstract

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...Continue Reading

References

Sep 6, 2001·Molecular Carcinogenesis·M KohdaM Oshimura
Jun 1, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Poul H B SorensenFrederic G Barr
Sep 3, 2004·Cancer Research·Jingsong ZhangTimothy J Triche
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Aug 15, 2008·Cancer Research·Jérôme KucharczakCécile Gauthier-Rouvière
Mar 6, 2009·Genome Biology·Ben LangmeadSteven L Salzberg
Apr 3, 2009·Cancer Research·Koichi NishijoCharles Keller
Mar 8, 2011·The Biochemical Journal·Hwajin JungEek-hoon Jho
May 4, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Tohru HosoyamaCharles Keller
Feb 4, 2014·Genome Biology·Charity W LawGordon K Smyth
Apr 8, 2014·Proceedings of the National Academy of Sciences of the United States of America·Eleanor Y ChenDavid M Langenau
Oct 10, 2014·Expert Opinion on Therapeutic Targets·Mieke Dewerchin, Peter Carmeliet
Jun 14, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Julie J G KephartCorinne M Linardic
Sep 4, 2015·International Journal of Molecular Medicine·Linghong Wu, Ying Zhu
Sep 10, 2015·Critical Reviews in Oncogenesis·Jack F ShernJaved Khan
Oct 1, 2015·Sarcoma·Xin SunZhenfeng Duan
Nov 2, 2016·The Journal of Clinical Investigation·Maria BöhmBeat W Schäfer
Nov 15, 2016·Oncology Reports·Osamu OtabeHajime Hosoi
Apr 30, 2017·Nature Reviews. Cancer·Gina M SizemoreMichael C Ostrowski
Oct 31, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Thanh Hung Nguyen, Frederic G Barr
Jan 9, 2019·Nature Reviews. Disease Primers·Stephen X SkapekDouglas S Hawkins
Feb 14, 2019·Expert Opinion on Therapeutic Targets·Tyler S McCannPaul Jedlicka
Jun 22, 2019·Pediatric Blood & Cancer·Marielle E YoheDavid M Langenau
Jun 25, 2020·Genes & Cancer·Lays Martin SobralPaul Jedlicka

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Citations

May 18, 2021·Computational and Structural Biotechnology Journal·Qingyu ChengXiaoyuan Song

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Methods Mentioned

BETA
xenograft
ChIP
RNAseq
acetylation
immunoprecipitation

Software Mentioned

rsem
gsea
FP
Integrated Genomics Viewer ( IGV )
bowtie2
DAVID
limma
RMS

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