ARID1A-deficient cells require HDAC6 for progression of endometrial carcinoma

dc.contributor.authorMegino-Luque, Cristina
dc.contributor.authorSisó, Pol
dc.contributor.authorMota Martorell, Natàlia
dc.contributor.authorNavaridas Fernández de Bobadilla, Raúl
dc.contributor.authorde la Rosa, Inés
dc.contributor.authorUrdanibia, Izaskun
dc.contributor.authorAlbertí Valls, Manel
dc.contributor.authorSantacana Espasa, Maria
dc.contributor.authorPinyol, Miquel
dc.contributor.authorBonifaci, Núria
dc.contributor.authorMacià Armengol, Anna
dc.contributor.authorLlobet Navàs, David
dc.contributor.authorGatius Calderó, Sònia
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorEritja Sánchez, Núria
dc.description.abstractAT-rich interactive domain-containing protein 1A (ARID1A) loss-of-function mutation accompanied by a loss of ARID1A protein expression is frequently observed in endometrial carcinomas. However, the molecular mechanisms linking these genetic changes to the altered pathways regulating tumour initiation, maintenance and/or progression remain poorly understood. Thus, the main aim of this study was to analyse the role of ARID1A loss of function in endometrial tumorigenesis. Here, using different endometrial in vitro and in vivo models, such as tumoral cell lines, 3D primary cultures and metastatic or genetically modified mouse models, we show that altered expression of ARID1A is not enough to initiate endometrial tumorigenesis. However, in an established endometrial cancer context, ARID1A loss of function accelerates tumoral progression and metastasis through the disruption of the G2/M cell cycle checkpoint and ATM/ATR-mediated DNA damage checkpoints, increases epithelial cell proliferation rates and induces epithelial mesenchymal transition through the activation of histone deacetylase 6 (HDAC6). Next, we demonstrated that the inhibition of HDAC6 function, using the HDAC6-specific inhibitor ACY1215 or by transfection with HDAC6 short hairpin RNA (shRNA), can reverse the migratory and invasive phenotype of ARID1A-knockdown cells. Further, we also show that inhibition of HDAC6 activity causes an apoptotic vulnerability to etoposide treatments in ARID1A-deficient cells. In summary, the findings exposed in this work indicate that the inhibition of HDAC6 activity is a potential therapeutic strategy for patients suffering from ARID1A-mutant endometrial cancer diagnosed in advanced stages.ca_ES
dc.description.sponsorshipThis work has been funded by the Instituto de Salud Carlos III (ISCIII) through the projects PI20/00502, CP19/00025, CB16/12/00231, PI16/00692, PI18/00573 CP17/00063, PI18/00795 and PI21/00672, by the Ministry of Economy and Competitiveness (MINECO) through the project RTC-2017-6261-1 (Cofounded by European Regional Development Fund (ERDF) ‘a way to make Europe’ and ESF ‘Investing in your future’) and the Fundacion DEXEUS Salud de la Mujer PV100-41. We also thank the Grups consolidats de la Generalitat de Catalunya (2017SGR1368) and the Asociación Española Contra el Cáncer (AECC; Grupos Estables 2018: GCTRA1804MATI and LABAE19004LLOB). NE (MS19/00025) and DL-N (MS17/00063) are recipients of a Miguel Servet research scheme (Cofounded by the European Social Fund (ESF), ‘investing in your future’). CM-L holds a predoctoral fellowship from Generalitat de Catalunya (2020FI_B2 00099) and a predoctoral fellowship ‘Ajuts 2021 de Promoció de la Recerca en Salut-9ª edició’ from IRBLleida/Diputació de Lleida. MA-V holds a fellowship from CIBERONC ‘Ayudas para contratos de inciación a la investigación’. We also thank the CERCA programme/Generalitat de Catalunya for institutional support.ca_ES
dc.publisherFederation of European Biochemical Societiesca_ES
dc.publisherJohn Wiley & Sonsca_ES
dc.relation.isformatofReproducció del document publicat a:
dc.relation.ispartofMolecular Oncology, 2022, vol. 16, num. 11, p. 2235-2259ca_ES
dc.rightscc-by (c) Authors, 2022ca_ES
dc.subjectEndometrial cancerca_ES
dc.titleARID1A-deficient cells require HDAC6 for progression of endometrial carcinomaca_ES
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