Cancers of childhood have unique pathobiology,
including origins in developing or otherwise immature tissues, relative paucity
of mutations, extensive epigenetic dysregulation, and clinically aggressive
behavior, including early and frequent metastasis. Ewing Sarcoma is a
prototypical pediatric cancer arising in a stem or stem-like cell, usually in
bone, with a high propensity for metastatic dissemination. A subset of patients
presenting with clinically localized disease can be cured with multi-agent
conventional chemotherapy, but patients presenting with metastasis or
recurrence face poor outcomes and currently have few treatment options. The
need to identify new therapeutic approaches for this disease is thus easy to
justify. Ewing Sarcoma has a largely quiescent genome, save for recurrent
chromosomal translocations that yield fusion proteins with potent oncogenic
activity. Such fusions generally consist of the N-terminus of the EWS protein
and the C-terminus, including the DNA-binding domain, of an Ets transcription
factor. EWS/Ets fusions, EWS/Fli1 being
the most common, result in profound alterations of gene expression in the cell,
through transcriptional, as well as other, mechanisms.
EWS/Ets fusions represent logical
therapeutic targets in Ewing Sarcoma. However, to date, such targeting has
proven difficult. Moreover, while EWS/Ets fusions are established drivers of
oncogenic transformation and tumorigenesis, recent studies suggest that they
are not the chief drivers of metastasis. Indeed, at present, the mechanistic
basis of the known high metastatic propensity of Ewing Sarcoma is poorly
understood. Recently, our laboratory has identified the Jumonji-domain histone
demethylase KDM3A as a new, therapeutically targetable, pro-tumorigenic and
pro-metastatic factor downstream of EWS/Fli1. KDM3A is an epigenetic regulator
belonging to the histone mark “eraser” class, with specificity for H3K9 methyl
1 and 2 histone marks. These marks are generally associated with
transcriptional repression, but molecular mechanistic details of how they
contribute to control of gene expression are not well understood.
Currently, our laboratory
is broadly interested in further understanding the biology of Jumonji-domain
histone demethylases in regulation of gene expression and cancer phenotypes in
Ewing Sarcoma, and in leveraging this information to try to improve patient
outcomes. Specific questions include: 1) How do KDM3A and other JHDMs impact relevant
cancer phenotypes, and what pathways are involved? 2) Is pharmacologic
inhibition of JHDMs a viable therapeutic strategy, and if so, which JHDMs are
key to inhibit? 3) What are the molecular mechanisms by which KDM3A, and other
JHDMs, control target gene expression? 4) Are these effects/mechanisms of
relevance in other pediatric cancers? To answer these questions, our laboratory
uses a variety of molecular, biochemical, cell culture and in vivo approaches,
with the ultimate goals of advancing the understanding of Ewing Sarcoma
pathogenesis and harnessing such knowledge to lessen the clinical burden of
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JK, Sechler M, Winn RA and Jedlicka P. The histone demethylase KDM3A is a
microRNA-22-regulated tumor promoter in Ewing Sarcoma. Oncogene (2013).
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Parrish JK, Spoelstra NS, Joyal T, Richer JK and Jedlicka P.
Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes.
PLoS One (2015).
- Sechler M, Parrish JK, Birks DK and Jedlicka P. The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis. Oncogene (2017).
- Moore C, Parrish JK and Jedlicka P. MiR-193b, downregulated in Ewing Sarcoma, targets the ErbB4 oncogene to inhibit anchorage-independent growth. PLoS ONE (2017).
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- Parrish JK, McCann TS, Sechler M, Sobral LM, Ren W, Jones KL, Tan AC and Jedlicka P. The Jumonji-domain histone demethylase inhibitor JIB-04 deregulates oncogenic programs and increases DNA damage in Ewing Sarcoma, resulting in impaired cell proliferation and survival, and reduced tumor growth. Oncotarget (2018).
- McCann TS, Sobral LM, Self C, Hsieh J, Sechler M and Jedlicka P. Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview. Expert Opinion on Therapeutic Targets (2019).