Increased Efficacy of Histone Methyltransferase G9a Inhibitors Against <i>MYCN</i>-Amplified Neuroblastoma.

Bellamy, J; Szemes, M; Melegh, Z; Dallosso, A; Kollareddy, M; Catchpoole, D; Malik, K

Increased Efficacy of Histone Methyltransferase G9a Inhibitors Against <i>MYCN</i>-Amplified Neuroblastoma.

Bellamy, J Szemes, M Melegh, Z Dallosso, A Kollareddy, M Catchpoole, D Malik, K

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Publisher:: Frontiers Media SA
Publication Type:: Journal Article
Citation:: Frontiers in oncology, 2020, 10, pp. 818
Issue Date:: 2020-01

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Field	Value	Language
dc.contributor.author	Bellamy, J
dc.contributor.author	Szemes, M
dc.contributor.author	Melegh, Z
dc.contributor.author	Dallosso, A
dc.contributor.author	Kollareddy, M
dc.contributor.author	Catchpoole, D
dc.contributor.author	Malik, K
dc.date.accessioned	2021-02-14T19:40:38Z
dc.date.available	2020-04-27
dc.date.available	2021-02-14T19:40:38Z
dc.date.issued	2020-01
dc.identifier.citation	Frontiers in oncology, 2020, 10, pp. 818
dc.identifier.issn	2234-943X
dc.identifier.issn	2234-943X
dc.identifier.uri	http://hdl.handle.net/10453/146081
dc.description.abstract	Targeted inhibition of proteins modulating epigenetic changes is an increasingly important priority in cancer therapeutics, and many small molecule inhibitors are currently being developed. In the case of neuroblastoma (NB), a pediatric solid tumor with a paucity of intragenic mutations, epigenetic deregulation may be especially important. In this study we validate the histone methyltransferase G9a/EHMT2 as being associated with indicators of poor prognosis in NB. Immunological analysis of G9a protein shows it to be more highly expressed in NB cell-lines with <i>MYCN</i> amplification, which is a primary determinant of dismal outcome in NB patients. Furthermore, G9a protein in primary tumors is expressed at higher levels in poorly differentiated/undifferentiated NB, and correlates with high EZH2 expression, a known co-operative oncoprotein in NB. Our functional analyses demonstrate that siRNA-mediated G9a depletion inhibits cell growth in all NB cell lines, but, strikingly, only triggers apoptosis in NB cells with <i>MYCN</i> amplification, suggesting a synthetic lethal relationship between G9a and MYCN. This pattern of sensitivity is also evident when using small molecule inhibitors of G9a, UNC0638, and UNC0642. The increased efficacy of G9a inhibition in the presence of MYCN-overexpression is also demonstrated in the SHEP-21N isogenic model with tet-regulatable MYCN. Finally, using RNA sequencing, we identify several potential tumor suppressor genes that are reactivated by G9a inhibition in NB, including the <i>CLU, FLCN, AMHR2</i>, and <i>AKR1C1-3</i>. Together, our study underlines the under-appreciated role of G9a in NB, especially in <i>MYCN</i>-amplified tumors.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	Frontiers Media SA
dc.relation.ispartof	Frontiers in oncology
dc.relation.isbasedon	10.3389/fonc.2020.00818
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.title	Increased Efficacy of Histone Methyltransferase G9a Inhibitors Against <i>MYCN</i>-Amplified Neuroblastoma.
dc.type	Journal Article
utslib.citation.volume	10
utslib.location.activity	Switzerland
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	open_access	*
dc.date.updated	2021-02-14T19:39:53Z
pubs.publication-status	Published
pubs.volume	10

Abstract:

Targeted inhibition of proteins modulating epigenetic changes is an increasingly important priority in cancer therapeutics, and many small molecule inhibitors are currently being developed. In the case of neuroblastoma (NB), a pediatric solid tumor with a paucity of intragenic mutations, epigenetic deregulation may be especially important. In this study we validate the histone methyltransferase G9a/EHMT2 as being associated with indicators of poor prognosis in NB. Immunological analysis of G9a protein shows it to be more highly expressed in NB cell-lines with MYCN amplification, which is a primary determinant of dismal outcome in NB patients. Furthermore, G9a protein in primary tumors is expressed at higher levels in poorly differentiated/undifferentiated NB, and correlates with high EZH2 expression, a known co-operative oncoprotein in NB. Our functional analyses demonstrate that siRNA-mediated G9a depletion inhibits cell growth in all NB cell lines, but, strikingly, only triggers apoptosis in NB cells with MYCN amplification, suggesting a synthetic lethal relationship between G9a and MYCN. This pattern of sensitivity is also evident when using small molecule inhibitors of G9a, UNC0638, and UNC0642. The increased efficacy of G9a inhibition in the presence of MYCN-overexpression is also demonstrated in the SHEP-21N isogenic model with tet-regulatable MYCN. Finally, using RNA sequencing, we identify several potential tumor suppressor genes that are reactivated by G9a inhibition in NB, including the CLU, FLCN, AMHR2, and AKR1C1-3. Together, our study underlines the under-appreciated role of G9a in NB, especially in MYCN-amplified tumors.

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http://hdl.handle.net/10453/146081