Epigenetic Changes at the Birc5 Promoter Induced by YM155 in Synovial Sarcoma
by
Aleksander Mika 1
, Sarah E. Luelling 2, Adriene Pavek 2, Christopher Nartker 2, Alexandra L. Heyneman 2, Kevin B. Jones 1,* and Jared J. Barrott 1,2,*
Aleksander Mika 1, Sarah E. Luelling 2, Adriene Pavek 2, Christopher Nartker 2, Alexandra L. Heyneman 2, Kevin B. Jones 1,* and Jared J. Barrott 1,2,*
1
Departments of Orthopedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
2
Department of Biomedical and Pharmaceutical Sciences, Idaho State University, Pocatello, ID 83209, USA
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(3), 408; https://doi.org/10.3390/jcm8030408
Received: 12 February 2019 / Revised: 20 March 2019 / Accepted: 21 March 2019 / Published: 24 March 2019
(This article belongs to the Section Oncology)
YM155 is an anti-cancer therapy that has advanced into 11 different human clinical trials to treat various cancers. This apoptosis-inducing therapy indirectly affects the protein levels of survivin (gene: Birc5), but the molecular underpinnings of the mechanism remain largely unknown. Synovial sarcoma is a rare soft-tissue malignancy with high protein expression of survivin. We investigated whether YM155 would be a viable therapeutic option to treat synovial sarcoma. YM155 therapy was applied to human synovial sarcoma cell lines and to a genetically engineered mouse model of synovial sarcoma. We discovered that YM155 exhibited nanomolar potency against human synovial sarcoma cell lines and the treated mice with synovial sarcoma demonstrated a 50% reduction in tumor volume compared to control treated mice. We further investigated the mechanism of action of YM155 by looking at the change of lysine modifications of the histone tails that were within 250 base pairs of the Birc5 promoter. Using chromatin immunoprecipitation (ChIP)-qPCR, we discovered that the histone epigenetic marks of H3K27 for the Birc5 promoter changed upon YM155 treatment. H3K27me3 and H3K27ac increased, but the net result was decreased Birc5/survivin expression. Furthermore, the combination of molecular events resulted in caspase 3/7/8 upregulation and death of the sarcoma cells.
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Keywords:
survivin; Birc5; synovial sarcoma; YM155; epigenetics
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Mika, A.; Luelling, S.E.; Pavek, A.; Nartker, C.; Heyneman, A.L.; Jones, K.B.; Barrott, J.J. Epigenetic Changes at the Birc5 Promoter Induced by YM155 in Synovial Sarcoma. J. Clin. Med. 2019, 8, 408.
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