EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer Leigh Ellis, Beatriz German, Katherine Morel, Teia Noel, Nadia Boufaied, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7360528/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype. Biological sciences/Cancer/Urological cancer/Prostate cancer Biological sciences/Cancer EZH2 PI3K mTOR Phenotypic Plasticity Translation. Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementTables.xlsx Supplementary dataset Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7360528","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":503185098,"identity":"0119bd51-f5a7-4696-ba93-baec287b7511","order_by":0,"name":"Leigh Ellis","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsklEQVRIiWNgGAWjYBACPgbmxgMJDDZAZgKRWtgYGBuAWtJI1cLAcJgULeyNDQce/Dkvb86e+4Dh455aIrTwHGw4kNh223Bnz3MDxhnPjhOhRSIRqKXhdoLBjTQGZp4Dx4jQIv8Q6P0/50jRIgEKMbYDMC01RGjhATmsLRnol2cMB2ccOEBYCz/74YMPf/yxA4ZYGuODDwfqCGuBAwMgPgCJIFK0AAEptoyCUTAKRsFIAQDygj98T542LwAAAABJRU5ErkJggg==","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Leigh","middleName":"","lastName":"Ellis","suffix":""},{"id":503185099,"identity":"a7aeca20-b42b-42db-8ab6-f9b494069019","order_by":1,"name":"Beatriz German","email":"","orcid":"","institution":"Center for Prostate Disease Research (CPDR)","correspondingAuthor":false,"prefix":"","firstName":"Beatriz","middleName":"","lastName":"German","suffix":""},{"id":503185100,"identity":"0acd7e75-e314-488d-aa5e-aa0d6ef215b0","order_by":2,"name":"Katherine Morel","email":"","orcid":"https://orcid.org/0000-0002-7968-4032","institution":"University of Adelaide","correspondingAuthor":false,"prefix":"","firstName":"Katherine","middleName":"","lastName":"Morel","suffix":""},{"id":503185101,"identity":"f5aa7c59-486a-40d9-a444-27bdc8bdd16f","order_by":3,"name":"Teia Noel","email":"","orcid":"","institution":"Cedars-Sinai Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Teia","middleName":"","lastName":"Noel","suffix":""},{"id":503185102,"identity":"1e08b13e-e531-41fe-ba92-8556a865317b","order_by":4,"name":"Nadia Boufaied","email":"","orcid":"","institution":"McGill University","correspondingAuthor":false,"prefix":"","firstName":"Nadia","middleName":"","lastName":"Boufaied","suffix":""},{"id":503185103,"identity":"e0b769d4-6a3d-4f15-92c7-72e9ac7b999e","order_by":5,"name":"Deborah Burkhart","email":"","orcid":"https://orcid.org/0000-0002-7457-6032","institution":"Dana-Farber Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Deborah","middleName":"","lastName":"Burkhart","suffix":""},{"id":503185104,"identity":"ce48150c-d037-44ce-b4a1-c504dec8f690","order_by":6,"name":"Sujun Chen","email":"","orcid":"https://orcid.org/0000-0002-1941-3951","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sujun","middleName":"","lastName":"Chen","suffix":""},{"id":503185105,"identity":"d8c4f847-6760-4715-a600-f43a8ee0d1f9","order_by":7,"name":"Felipe Dezem","email":"","orcid":"","institution":"St.Jude Children's Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Felipe","middleName":"","lastName":"Dezem","suffix":""},{"id":503185106,"identity":"b893bbde-c78f-4f26-8905-84c9388729b2","order_by":8,"name":"Xintao Qiu","email":"","orcid":"","institution":"Dana Farber Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Xintao","middleName":"","lastName":"Qiu","suffix":""},{"id":503185107,"identity":"b31e4688-3bbd-4091-90fa-cc0ef94d23c0","order_by":9,"name":"Henry Long","email":"","orcid":"https://orcid.org/0000-0001-6849-6629","institution":"Dana-Farber Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Henry","middleName":"","lastName":"Long","suffix":""},{"id":503185108,"identity":"a0a76ea4-8a9d-457f-bbea-6fe4053c1dbb","order_by":10,"name":"Stefan DiFazio","email":"","orcid":"","institution":"Center for Prostate Disease Research","correspondingAuthor":false,"prefix":"","firstName":"Stefan","middleName":"","lastName":"DiFazio","suffix":""},{"id":503185109,"identity":"221812b2-d737-4cd2-9ea5-a604d16b12e6","order_by":11,"name":"Sylvan Baca","email":"","orcid":"https://orcid.org/0000-0002-4087-8606","institution":"Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Sylvan","middleName":"","lastName":"Baca","suffix":""},{"id":503185110,"identity":"116b2f12-eba5-4dc3-b802-26e28b759937","order_by":12,"name":"Ayesha Shafi","email":"","orcid":"https://orcid.org/0000-0003-0335-638X","institution":"Center for Prostate Disease Research (CPDR) Henry M. 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