CUL4 Lung Adenocarcinomas Are Dependent on the CUL4-p21 Ubiquitin Signaling for Proliferation and Survival.

TitleCUL4 Lung Adenocarcinomas Are Dependent on the CUL4-p21 Ubiquitin Signaling for Proliferation and Survival.
Publication TypeJournal Article
Year of Publication2021
AuthorsWang Y, Yan F, Nasar A, Chen Z-S, Altorki NKhaled, Stiles B, Narula N, Zhou P
JournalAm J Pathol
Date Published2021 09
KeywordsAdenocarcinoma of Lung, Animals, Biomarkers, Cell Proliferation, Cell Survival, Cullin Proteins, Cyclin-Dependent Kinase Inhibitor p21, Disease Progression, Drug Resistance, Neoplasm, Female, Heterografts, Humans, Lung Neoplasms, Mice, Mice, Nude, Prognosis, Signal Transduction, Ubiquitin

Cullin (CUL) 4A and 4B ubiquitin ligases are often highly accumulated in human malignant neoplasms and are believed to possess oncogenic properties. However, the underlying mechanisms by which CUL4A and CUL4B promote pulmonary tumorigenesis remain largely elusive. This study reports that CUL4A and CUL4B are highly expressed in patients with non-small cell lung cancer (NSCLC), and their high expression is associated with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. Depletion of CUL4A (CUL4A) or CUL4B (CUL4B) leads to cell cycle arrest at G and loss of proliferation and viability of NSCLC cells in culture and in a lung cancer xenograft model, suggesting that CUL4A and 4B are oncoproteins required for tumor maintenance of certain NSCLCs. Mechanistically, increased accumulation of the cell cycle-dependent kinase inhibitor p21/Cip1/WAF1 was observed in lung cancer cells on CUL4 silencing. Knockdown of p21 rescued the G arrest of CUL4A or CUL4B NSCLC cells, and allowed proliferation to resume. These findings reveal that p21 is the primary downstream effector of lung adenocarcinoma dependence on CUL4, highlight the notion that not all substrates respond equally to abrogation of the CUL4 ubiquitin ligase in NSCLCs, and imply that CUL4A/CUL4B may serve as a prognostic marker and therapeutic target for patients with NSCLC.

Alternate JournalAm J Pathol
PubMed ID34119472
PubMed Central IDPMC8420861
Grant ListR01 CA213992 / CA / NCI NIH HHS / United States
R01 CA221152 / CA / NCI NIH HHS / United States
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