Wang Y, Yan F, Nasar A, et al. - To gain insights into the underlying mechanisms whereby CUL4A and CUL4B (cullin 4A and 4B ubiquitin ligases) promote lung tumorigenesis, this study was undertaken. Researchers found high expression of both CUL4A and CUL4B in non-small cell lung cancer (NSCLC) patients, and also a link of high expression of both with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. CUL4A and 4B were suggested as oncoproteins needed for tumor maintenance of certain NSCLC, this inference was based on the observed cell cycle arrest at G1 as well as loss of proliferation and viability of NSCLC cells consequent to depletion of CUL4A (CUL4A ^k/d ) or CUL4B (CUL4B ^k/d ), as evident both in culture and in a lung cancer xenograft model. In this study, p21 was identified as the primary downstream effector of lung adenocarcinoma dependence on CUL4. Findings emphasize the notion that all substrates do not respond equally to abrogation of the CUL4 ubiquitin ligase in NSCLCs. Based on the results, it was inferred that CUL4A ^high CUL4B ^high may represent a prognostic marker as well as a treatment target for NSCLC cases.