The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies

Our plain-English summary of The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies, by J. Hannah, P.B. Zhou (Chinese Journal of Cancer, 2013).

The study

• Authors: J. Hannah, P.B. Zhou
• Journal: Chinese Journal of Cancer
• Published: 2013;32(9):478-82
• Type of article: Review
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cullin 4A (CUL4A) is an E3 ubiquitin ligase that directly affects DNA repair and cell cycle progression by targeting substrates including damage-specific DNA-binding protein 2 (DDB2), xeroderma pigmentosum complementation group C (XPC), chromatin licensing and DNA replication factor 1 (Cdt1), and p21. Recent work from our laboratory has shown that Cul4a-deficient mice have greatly reduced rates of ultraviolet-induced skin carcinomas. On a cellular level, Cul4a-deficient cells have great capacity for DNA repair and demonstrate a slow rate of proliferation due primarily to increased expression of DDB2 and p21, respectively. This suggests that CUL4A promotes tumorigenesis (as well as accumulation of skin damage and subsequent premature aging) by limiting DNA repair activity and expediting S phase entry. In addition, CUL4A has been found to be up-regulated via gene amplification or overexpression in breast cancers, hepatocellular carcinomas, squamous cell carcinomas, adrenocortical carcinomas, childhood medulloblastomas, and malignant pleural mesotheliomas. Because of its oncogenic activity in skin cancer and up-regulation in other malignancies, CUL4A has arisen as a potential candidate for targeted therapeutic approaches. In this review, we outline the established functions of CUL4A and discuss the E3 ligase's emergence as a potential driver of tumorigenesis.

In plain English

This article was a short review by two researchers at Weill Cornell Medical College in New York. It did not study asbestos or people exposed to asbestos. It described CUL4A, a protein that marks other proteins for breakdown. Its targets include two DNA repair proteins (DDB2 and XPC) and a protein that delays cell division (p21). The authors summarized their own laboratory's earlier work in mice and mouse cells. In mouse cells lacking CUL4A, DDB2, XPC and p21 lasted significantly longer, and the cells showed a strong ability to repair ultraviolet-induced DNA damage. After ultraviolet damage, a pause in cell division lasted about 4 to 6 hours longer than in normal cells. When mice were exposed to UVB light, all control mice developed squamous cell skin carcinomas between 28 and 48 weeks. Mice lacking CUL4A in the skin were essentially resistant. The review also noted that other research groups had reported increased CUL4A in several cancers, including malignant pleural mesotheliomas. The authors concluded that CUL4A is an enticing potential therapeutic target in treating cancer and premature aging.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review article summarizing the known functions of the CUL4A protein, drawing mainly on the authors' own earlier laboratory study in mice and mouse cells
• Who was studied: No human population. The earlier laboratory work described used mice lacking the Cul4a gene, including a strain in which the gene could be removed specifically in the skin, and mouse embryonic fibroblast cells
• Exposure: Ultraviolet (UVB) irradiation in mice and cells. No asbestos or fiber exposure was studied
• Main results:
  • In mouse skin and mouse embryonic fibroblast cells lacking Cul4a, the DNA damage response proteins DDB2, XPC and p21 lasted significantly longer
  • In Cul4a-deficient mouse embryonic fibroblasts, cell cycle arrest after UV damage lasted approximately 4 to 6 hours longer than in normal (wild-type) cells
  • All control mice exposed to UVB developed squamous cell carcinomas between 28 and 48 weeks, while mice lacking Cul4a in the skin were essentially resistant to UVB-induced skin cancer
  • The authors reported that, in their studies, Cul4a-deficient mice did not show any adverse phenotypes
  • Citing genomic analyses by other research groups (not this article's own work), the review stated that CUL4A is up-regulated in several cancers, including malignant pleural mesotheliomas
• The authors' conclusion: The authors concluded that CUL4A is an enticing potential therapeutic target in treating cancer and premature aging, and predicted that loss of CUL4A would have minimal effects in humans

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Carcinogenesis, Squamous Cell Carcinoma, Pleural Mesothelioma.

Related studies

• An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma — A. Linton, Y.Y. Cheng, et al. (2014)
• Interleukin-6 as a therapeutic target in candidate inflammatory diseases — N. Nishimoto (2010)
• Cul4A is an oncogene in malignant pleural mesothelioma — M.S. Hung, J.H. Mao, et al. (2011)
• Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma — Y.L. Yang, J. Ni, et al. (2015)
• KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma — S. Cregan, L. McDonagh, et al. (2016)
• CD30 is a potential therapeutic target in malignant mesothelioma — S. Dabir, A. Kresak, et al. (2015)

Browse return to medical research.