Journal
NUCLEIC ACIDS RESEARCH
Volume 50, Issue 17, Pages 9838-9857Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac766
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Funding
- Spanish Ministry of Economy and Competitiveness [PID2020-118516GB-I00]
- Junta de Andalucia [P18-FR-1962, BIO-321]
- Fundacion Vencer El Cancer (VEC)
- European Union FEDER 'A way to build Europe' program
- FEDER/Ministerio de Ciencia e Innovacion -Agencia Estatal de Investigacion [RTI2018-094005-B-I00]
- Deutsche Jose Carreras Leukamie Stiftung [DJCLS 14R/2018, AGAUR 2017-SGR-305]
- Fundacio La Marato de TV3 [257/C/2019]
- Spanish Ministry of Science and Innovation
- Spanish Ministry of Education
- AGAUR FI-2010 fellowship
- Marie Sklodowska Curie Training network 'INTERCEPT-MDS' [H2020-MSCA-ITN-2020-953407]
- Junta de Andalucia
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The study reveals that PHF14 and HMG20A cooperate in regulating pathways involved in epithelial-mesenchymal plasticity, impacting cell migration, invasion, and cell-cell adhesion abilities. The PHF14-HMG20A complex modulates the Hippo pathway through direct interaction with the TEAD1 transcription factor.
High mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an amino-terminal, intrinsically disordered domain with transactivation activity; ii) an HMG box with higher binding affinity for double-stranded, four-way-junction DNA than for linear DNA; and iii) a long coiled-coil domain. Our proteomic study followed by a deletion analysis and structural modeling demonstrates that HMG20A forms a complex with the histone reader PHF14, via the establishment of a two-stranded alpha-helical coiled-coil structure. siRNA-mediated knockdown of either PHF14 or HMG20A in MDA-MB-231 cells causes similar defects in cell migration, invasion and homotypic cell-cell adhesion ability, but neither affects proliferation. Transcriptomic analyses demonstrate that PHF14 and HMG20A share a large subset of targets. We show that the PHF14-HMG20A complex modulates the Hippo pathway through a direct interaction with the TEAD1 transcription factor. PHF14 or HMG20A deficiency increases epithelial markers, including E-cadherin and the epithelial master regulator TP63 and impaired normal TGF beta-trigged epithelial-to-mesenchymal transition. Taken together, these data indicate that PHF14 and HMG20A cooperate in regulating several pathways involved in epithelial-mesenchymal plasticity.
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