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

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 {micro}Map 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.