{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:37:19Z","timestamp":1785411439173,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,4]]},"group-title":"Cancer Biology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T00:00:00Z","timestamp":1759536000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"award":["1R35GM150765"],"award-info":[{"award-number":["1R35GM150765"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Transcription factors (TFs) have long been aspirational therapeutic targets for the treatment of diseases, as their dysregulation is a common mechanism for altered cell states. Despite this, many TFs implicated in disease have disordered structures and lack canonical binding pockets, rendering them non-trivial targets for small molecule-based therapies. Directly inhibiting TF function has proven difficult, but indirect inhibition by targeting the effector molecules that modulate TF function is a promising, yet underexplored, alternative approach. Here we report a strategy for capturing cancer-specific protein-protein interactions using context-dependent \u00b5Map photoproximity labeling. Using an intein-based method for catalyst conjugation in biochemically intact nuclei, we demonstrate that we can capture unique protein interactomes of c-Myc in healthy and cancerous prostate cell lines, and that these unique interactors can be mined to identify druggable vulnerabilities. We find that a cancer specific Myc interactor, SLK, selectively promotes c-Myc stabilization at the protein level, drives epithelial morphology, and is essential for tumorigenesis, validating it as a viable therapeutic target. Importantly, this stabilization is driven by a change in SLK splicing rather than expression at the protein or RNA levels. Furthermore, analysis of cancer patient data shows a strong correlation between this splice isoform and expression of c-Myc targets, suggesting this novel regulatory axis is operative across human cancer.<\/jats:p>","DOI":"10.1101\/2025.10.02.680136","type":"posted-content","created":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T04:55:22Z","timestamp":1759640122000},"source":"Crossref","is-referenced-by-count":2,"title":["Photoproximity labeling of c-Myc reveals SLK as a cancer specific co-regulator"],"prefix":"10.64898","author":[{"given":"Ryan R.","family":"Milione","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey L.","family":"Wolfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara B.","family":"Linker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmeng Jasmine","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James V.","family":"Oakley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Nager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michalina","family":"Janiszewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-128X","authenticated-orcid":false,"given":"Ciaran P.","family":"Seath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025100811351061000_2025.10.02.680136v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0196-7"},{"key":"2025100811351061000_2025.10.02.680136v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00199-0"},{"key":"2025100811351061000_2025.10.02.680136v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.01.029"},{"key":"2025100811351061000_2025.10.02.680136v1.4","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.biocel.2017.12.020","article-title":"NF-\u03baB in the crosshairs: Rethinking an old riddle","volume":"95","year":"2018","journal-title":"Int. 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