The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways

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 TGFβ-trigged epithelial-to-mesenchymal transition. Taken together, these data indicate that PHF14 and HMG20A cooperate in regulating several pathways involved in epithelial–mesenchymal plasticity.
Research in the J.C. Reyes lab was funded by the Spanish Ministry of Economy and Competitiveness MCIN/AEI/10.13039/501100011033/ [PID2020-118516GB-I00]; Junta de Andalucía [P18-FR-1962 and BIO-321]; Fundación Vencer El Cancer (VEC); European Union FEDER ‘A way to build Europe’ program; research at Buschbeck lab is further supported by FEDER/Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación [RTI2018-094005-B-I00]; Marie Skłodowska Curie Training network ‘INTERCEPT-MDS’ [H2020-MSCA-ITN-2020–953407]; Deutsche José Carreras Leukämie Stiftung [DJCLS 14R/2018, AGAUR 2017-SGR-305]; Fundació La Marató de TV3 257/C/2019; CABIMER is a Center partially funded by the Junta de Andalucía; E.G.-M. is the recipient of an FPI fellowship from the Spanish Ministry of Science and Innovation; L.B.-C. is the recipient of an FPU fellowship from the Spanish Ministry of Education; M.P.M. was funded by an AGAUR FI-2010 fellowship. Funding for open access charge: Spanish Ministry of Economy and Competitiveness MCIN/AEI/10.13039/501100011033/ [PID2020-118516GB-I00].