TY - JOUR
T1 - Splicing factor proline- and glutamine-rich (SFPQ) protein regulates platinum response in ovarian cancer-modulating SRSF2 activity
AU - Pellarin, Ilenia
AU - Dall’Acqua, Alessandra
AU - Gambelli, Alice
AU - Pellizzari, Ilenia
AU - D’Andrea, Sara
AU - Sonego, Maura
AU - Lorenzon, Ilaria
AU - Schiappacassi, Monica
AU - Belletti, Barbara
AU - Baldassarre, Gustavo
N1 - Funding Information:
Acknowledgements We are grateful to the patients who consented to donating their samples. We thank Dr Benjamin Blencowe for providing the p54nrb and the SFPQ wild type and mutant expression vectors (through Addgene) and Dr Beatrice Eymin for providing the SRSF2 vector. We like to thank all members of the SCICC lab for fruitful scientific discussion, Dr Riccardo Bomben for helping us with the analysis of gene expression profiles and Dr Francesca Rossi for FACS analyses. This work was supported by grants from Ministero della Salute (RCR-2019-23669115 and RF-2016-02361040 to GB and GR-2016-02361041 to MS); Ministero degli Affari Esteri e Coop-erazione Internazionale (PGR01036 to GB), CRO-Ricerca Corrente core grant (linea 1); 5 × 1000 CRO Intramural to GB and Regione Friuli Venezia Giulia (POR-FERS TICHEP grant to GB).
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/28
Y1 - 2020/5/28
N2 - In epithelial ovarian cancer (EOC), response to platinum (PT)-based chemotherapy dictates subsequent treatments and predicts patients’ prognosis. Alternative splicing is often deregulated in human cancers and can be altered by chemotherapy. Whether and how changes in alternative splicing regulation could impact on the response of EOC to PT-based chemotherapy is still not clarified. We identified the splicing factor proline and glutamine rich (SFPQ) as a critical mediator of response to PT in an unbiased functional genomic screening in EOC cells and, using a large cohort of primary and recurrent EOC samples, we observed that it is frequently overexpressed in recurrent PT-treated samples and that its overexpression correlates with PT resistance. At mechanistic level, we show that, under PT treatment, SFPQ, in complex with p54nrb, binds and regulates the activity of the splicing factor SRSF2. SFPQ/p54nrb complex decreases SRSF2 binding to caspase-9 RNA, favoring the expression of its alternative spliced antiapoptotic form. As a consequence, SFPQ/p54nrb protects cells from PT-induced death, eventually contributing to chemoresistance. Overall, our work unveils a previously unreported SFPQ/p54nrb/SRSF2 pathway that in EOC cells plays a central role in regulating alternative splicing and PT-induced apoptosis and that could result in the design of new possible ways of intervention to overcome PT resistance.
AB - In epithelial ovarian cancer (EOC), response to platinum (PT)-based chemotherapy dictates subsequent treatments and predicts patients’ prognosis. Alternative splicing is often deregulated in human cancers and can be altered by chemotherapy. Whether and how changes in alternative splicing regulation could impact on the response of EOC to PT-based chemotherapy is still not clarified. We identified the splicing factor proline and glutamine rich (SFPQ) as a critical mediator of response to PT in an unbiased functional genomic screening in EOC cells and, using a large cohort of primary and recurrent EOC samples, we observed that it is frequently overexpressed in recurrent PT-treated samples and that its overexpression correlates with PT resistance. At mechanistic level, we show that, under PT treatment, SFPQ, in complex with p54nrb, binds and regulates the activity of the splicing factor SRSF2. SFPQ/p54nrb complex decreases SRSF2 binding to caspase-9 RNA, favoring the expression of its alternative spliced antiapoptotic form. As a consequence, SFPQ/p54nrb protects cells from PT-induced death, eventually contributing to chemoresistance. Overall, our work unveils a previously unreported SFPQ/p54nrb/SRSF2 pathway that in EOC cells plays a central role in regulating alternative splicing and PT-induced apoptosis and that could result in the design of new possible ways of intervention to overcome PT resistance.
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U2 - 10.1038/s41388-020-1292-6
DO - 10.1038/s41388-020-1292-6
M3 - Article
C2 - 32332923
AN - SCOPUS:85084076833
VL - 39
SP - 4390
EP - 4403
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 22
ER -