# DCAF12 Ubiquitin Ligase Promotes Lung Cancer Metastasis by Modulating the TRiC/CCT Chaperonin Complex

## TL;DR

This study shows how DCAF12 promotes lung cancer metastasis by modifying a chaperonin complex, offering a new therapeutic target.

## Contribution

The study reveals DCAF12's role in ubiquitin-mediated proteostatic reprogramming to drive metastasis.

## Key findings

- DCAF12 catalyzes non-degradative ubiquitination of TRiC/CCT subunits, enhancing chaperonin function.
- DCAF12 promotes cytoskeletal and oncogenic protein maturation, activating YAP, STAT3, and mTOR pathways.
- Targeting the DCAF12-TRiC/CCT axis with HSF1A inhibits metastasis in preclinical models.

## Abstract

Metastasis is the primary challenge in lung cancer treatment. Although proteostasis supports tumor growth, the mechanism by which ubiquitin ligases reprogram chaperone networks to drive metastasis is poorly understood. In this study, it is revealed that DDB1‐CUL4‐associated factor (DCAF12), a substrate receptor for CUL4‐RING ubiquitin ligases, regulates metastatic progression through ubiquitin‐mediated proteostatic reprogramming. DCAF12 depletion suppresses tumor cell migration and stemness in vitro and reduces pulmonary/hepatic metastasis in vivo. Mechanistically, DCAF12 catalyzes the non‐degradative ubiquitination of TRiC/CCT subunits, enhancing chaperonin assembly and folding of cytoskeletal effectors (β‐actin/tubulin) and oncogenic clients (STAT3/Raptor/mLST8), thereby activating the YAP, STAT3, and mTOR pathways. Both genetic knockdown and pharmacological blockade (via HSF1A) of this axis potently inhibit metastasis. Clinically, DCAF12 overexpression is correlated with YAP/STAT3 activation, advanced metastasis, and poor survival. Three key insights are revealed: 1) ubiquitination‐mediated TRiC/CCT regulation as a metastatic switch, 2) DCAF12 as an oncogenic proteostasis hub, and 3) therapeutic potential validated through multimodal targeting. These findings establish the DCAF12‐TRiC/CCT axis as a mechanistically novel target that simultaneously disrupts cytoskeletal dynamics and oncogenic signaling, making it a promising therapeutic strategy for metastatic lung cancer.

This study elucidates how DCAF12 facilitates non‐degradative ubiquitination to stabilize TRiC/CCT, thereby enhancing the folding capacity of chaperonins. This mechanism promotes the maturation of cytoskeletal proteins and activates key oncogenic drivers, including YAP, STAT3, and mTOR, ultimately driving metastatic progression in lung cancer. These findings underscore the therapeutic potential of targeting this axis using the TRiC/CCT inhibitor HSF1A.