Ubiquitination‐Driven Reprogramming of Proteostasis in Metastasis

ABSTRACT Metastasis, the leading cause of cancer‐related mortality, poses a fundamental proteostatic challenge, requiring rapid and precise proteome remodeling in response to stress. While ubiquitination is linked to protein degradation, our recent work uncovered a non‐canonical, metastasis‐promoting mechanism centered on DCAF12, a substrate receptor of the Cullin 4–RING ubiquitin ligase complex. DCAF12 mediates non‐degradative ubiquitination of TRiC/CCT chaperonin subunits, allosterically activating the chaperonin to enhance its assembly, stability, and folding capacity. This ubiquitination‐dependent activation circuit enables metastatic cells to efficiently fold and stabilize diverse pro‐metastatic proteins, thereby facilitating dynamic proteome reprogramming. Herein, we present the DCAF12–TRiC/CCT axis as a central regulatory component of this adaptive response, explore its evolutionary basis, and propose DCAF12 as a prototype for a broader class of “DCAFome” regulators of chaperone function. This mechanistic understanding establishes a direct rationale for therapeutically targeting this axis to disrupt adaptive proteostasis. Moreover, we outline a therapeutic paradigm termed “proteostatic stress creation.” This framework encompasses a spectrum of strategies, from precision protein–protein interaction inhibitors to state‐selective degraders of DCAF12 or its ubiquitinated chaperonin subunits. These approaches can potentially disrupt the DCAF12–TRiC/CCT axis, thereby undermining the proteostatic resilience that sustains advanced cancers.