MassIVE MSV000099411

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Photoproximity labeling of c-Myc reveals SLK as a cancer specific co-regulator

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Description

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 uMap 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. [doi:10.25345/C5K931K5G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: MYC ; c-Myc ; Proximity Labeling ; Global Proteomics ; Phospho Proteomics ; micro map ; uMap ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Ciaran Seath, University of Florida, USA
Submitting User: milione_ryan
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