TY - JOUR
T1 - CUL4high Lung Adenocarcinomas Are Dependent on the CUL4-p21 Ubiquitin Signaling for Proliferation and Survival
AU - Wang, Yannan
AU - Yan, Fan
AU - Nasar, Abu
AU - Chen, Zhe Sheng
AU - Altorki, Nasser Khaled
AU - Stiles, Brendon
AU - Narula, Navneet
AU - Zhou, Pengbo
N1 - Funding Information:
Supported by NIH grants R01 CA221152 (P.Z.) and R01 CA213992 (P.Z.), and the Weill Cornell Medicine Xiangya Medical School Exchange Program Fellowship (Y.W.).
Funding Information:
We thank Drs. Chenyi Yang and Yu Yan for guidance and assistance, Dr. Timothy McGraw for providing the cell line, the Weill Cornell Medicine Flow Cytometry and Advanced Microscope Core Facility, the Translational Research Program at Weill Cornell Medicine Pathology and Laboratory Medicine, and Dr. Bing He for expert assistance. Supported by NIH grants R01 CA221152 (P.Z.) and R01 CA213992 (P.Z.), and the Weill Cornell Medicine Xiangya Medical School Exchange Program Fellowship (Y.W.).
Publisher Copyright:
© 2021 American Society for Investigative Pathology
PY - 2021/9
Y1 - 2021/9
N2 - 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 (CUL4Ak/d) or CUL4B (CUL4Bk/d) leads to cell cycle arrest at G1 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 G1 arrest of CUL4Ak/d or CUL4Bk/d 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 CUL4Ahigh/CUL4Bhigh may serve as a prognostic marker and therapeutic target for patients with NSCLC.
AB - 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 (CUL4Ak/d) or CUL4B (CUL4Bk/d) leads to cell cycle arrest at G1 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 G1 arrest of CUL4Ak/d or CUL4Bk/d 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 CUL4Ahigh/CUL4Bhigh may serve as a prognostic marker and therapeutic target for patients with NSCLC.
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U2 - 10.1016/j.ajpath.2021.05.018
DO - 10.1016/j.ajpath.2021.05.018
M3 - Article
C2 - 34119472
AN - SCOPUS:85113760246
VL - 191
SP - 1638
EP - 1650
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 9
ER -