Abstract
A growing number of studies support a direct role for nuclear mTOR in gene regulation and chromatin structure. Still, the scarcity of known chromatin-bound mTOR partners limits our understanding of how nuclear mTOR controls transcription. Herein, comprehensive mapping of the mTOR chromatin-bound interactome in both androgen-dependent and -independent cellular models of prostate cancer (PCa) identifies a conserved 67-protein interaction network enriched for chromatin modifiers, transcription factors, and SUMOylation machinery. SUMO2/3 and nuclear pore protein NUP210 are among the strongest interactors, while the androgen receptor (AR) is the dominant androgen-inducible mTOR partner. Further investigation reveals that NUP210 facilitates mTOR nuclear trafficking, that mTOR and AR form a functional transcriptional module with the nucleosome remodeling and deacetylase (NuRD) complex, and that androgens specify mTOR-SUMO2/3 promoter-enhancer association. This work identifies a vast network of mTOR-associated nuclear complexes advocating innovative molecular strategies to modulate mTOR-dependent gene regulation with conceivable implications for PCa and other diseases.