TY - JOUR
T1 - Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality
AU - Sanese, Paola
AU - Fasano, Candida
AU - Buscemi, Giacomo
AU - Bottino, Cinzia
AU - Corbetta, Silvia
AU - Fabini, Edoardo
AU - Silvestri, Valentina
AU - Valentini, Virginia
AU - Disciglio, Vittoria
AU - Forte, Giovanna
AU - Lepore Signorile, Martina
AU - De Marco, Katia
AU - Bertora, Stefania
AU - Grossi, Valentina
AU - Guven, Ummu
AU - Porta, Natale
AU - Di Maio, Valeria
AU - Manoni, Elisabetta
AU - Giannelli, Gianluigi
AU - Bartolini, Manuela
AU - Del Rio, Alberto
AU - Caretti, Giuseppina
AU - Ottini, Laura
AU - Simone, Cristiano
N1 - Funding Information:
This work was supported by the Fondazione Puglia to P.S., by the Italian Association for Cancer Research (IG grant N. 23794 to C.S., IG grant N.19172 to A.D.R., IG 2018 grant N.21389 to L.O., IG 2018 grant N.21353 to G.C.), by the Italian Ministry of Health “Ricerca Corrente 2018–2020; 2019–2021” to C.S. and “Starting Grant” SG-2019-12371540 to P.S., by the Fondazione Cariplo to G.C., and by the Italian Ministry of Education, University and Research (MIUR) “ PRIN - Research Projects of National Relevance“ (PRIN 2017, n. 2017WNKSLRLS4 ) to C.S.
Publisher Copyright:
© 2020 The Author(s)
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10/23
Y1 - 2020/10/23
N2 - SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors.
AB - SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors.
KW - Cancer
KW - Cell Biology
KW - Molecular Biology
UR - http://www.scopus.com/inward/record.url?scp=85092342632&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092342632&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101604
DO - 10.1016/j.isci.2020.101604
M3 - Article
AN - SCOPUS:85092342632
VL - 23
JO - iScience
JF - iScience
SN - 2589-0042
IS - 10
M1 - 101604
ER -