2. Academic Validation
  3. DCAF12 Ubiquitin Ligase Promotes Lung Cancer Metastasis by Modulating the TRiC/CCT Chaperonin Complex

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

  • Adv Sci (Weinh). 2025 Oct 5:e09695. doi: 10.1002/advs.202509695.
Zhenyi Wang 1,  Huanhuan Huang 2,  Kaizong Huang 3,  Xiaowen Cui 2,  Leilei Wu 4,  Renyu Lin 5,  Zhe Zhao 6,  Hua Chen 7,  Cheng Zheng 1,  Weilin Jin 8,  Song Chen 9 10,  Jiayan Chen 11,  Yaping Xu 4,  Dongping Wei 1 2
Affiliations

Affiliations

  • 1 Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325015, China.
  • 2 Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, China.
  • 3 Department of Clinical Pharmacology Lab, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, China.
  • 4 Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
  • 5 Department of Otolaryngology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325015, China.
  • 6 Xuyi People's Hospital, Kangda College of Nanjing Medical University, Huai'an, Jiangsu, 211700, China.
  • 7 Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325015, China.
  • 8 Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, 730000, China.
  • 9 Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai'an, Jiangsu, 223300, China.
  • 10 Translational Research Institute of Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450053, China.
  • 11 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
PMID: 41047465 DOI: 10.1002/advs.202509695
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.

Keywords

DCAF12; TRiC/CCT complex; metastasis; proteostasis; ubiquitination.

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