Dishevelled-1 DIX and PDZ domain lysine residues regulate oncogenic Wnt signaling

Abstract

// Monica Sharma 1 , Isabel Castro-Piedras 1 , Fahmida Rasha 1 , Sabarish Ramachandran 2 , Souad R. Sennoune 2 , Kathryn Furr 1 , Sharilyn Almodovar 1 , Vadivel Ganapathy 2 , Matthew B. Grisham 1 , Rakhshanda Layeequr Rahman 3 and Kevin Pruitt 1 1 Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA 2 Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA 3 Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX, USA Correspondence to: Kevin Pruitt, email: [email protected] Keywords: dishevelled (DVL); post-translational modification; lysine residue; gene expression; chromatin immunoprecipitation (ChIP) Received: August 03, 2021     Accepted: September 24, 2021     Published: October 26, 2021 Copyright: © 2021 Sharma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT DVL proteins are central mediators of the Wnt pathway and relay complex input signals into different branches of the Wnt signaling network. However, molecular mechanism(s) that regulate DVL-mediated relay of Wnt signals still remains unclear. Here, for the first time, we elucidate the functional significance of three DVL-1 lysines (K/Lys) which are subject to post-translational acetylation. We demonstrate that K34 Lys residue in the DIX domain regulates subcellular localization of β-catenin, thereby influencing downstream Wnt target gene expression. Additionally, we show that K69 (DIX domain) and K285 (PDZ domain) regulate binding of DVL-1 to Wnt target gene promoters and modulate expression of Wnt target genes including CMYC , OCT4 , NANOG , and CCND1 , in cell line models and xenograft tumors. Finally, we report that conserved DVL-1 lysines modulate various oncogenic functions such as cell migration, proliferation, cell-cycle progression, 3D-spheroid formation and in-vivo tumor growth in breast cancer models. Collectively, these findings highlight the importance of DVL-1 domain-specific lysines which were recently shown to be acetylated and characterize their influence on Wnt signaling. These site-specific modifications may be subject to regulation by therapeutics already in clinical use (lysine deacetylase inhibitors such as Panobinostat and Vorinostat) or may possibly have prognostic utility in translational efforts that seek to modulate dysfunctional Wnt signaling.

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