Purpose: Recent studies have shown that the process of protein neddylation was 
abnormally activated in several human cancers. However, it is unknown whether 
and how UBE2F, a less characterized neddylation E2, regulates lung cancer cell 
survival, and whether and how NOXA, a proapoptotic protein, is ubiquitylated and 
degraded by which E3 and via which ubiquitin linkage.Experimental Design: 
Methods of immunohistochemistry and immunoblotting were utilized to examine 
UBE2F protein expression. The biological functions of UBE2F were evaluated by in 
vitro cell culture and in vivo xenograft models. The in vivo complex formation 
among UBE2F-SAG-CUL5-NOXA was measured by a pulldown assay. Polyubiquitylation 
of NOXA was evaluated by in vivo and in vitro ubiquitylation assays.Results: 
UBE2F is overexpressed in non-small cell lung cancer (NSCLC) and predicts poor 
patient survival. While UBE2F overexpression promotes lung cancer growth both in 
vitro and in vivo, UBE2F knockdown selectively inhibits tumor growth. By 
promoting CUL5 neddylation, UBE2F/SAG/CUL5 tri-complex activates CRL5 
(Cullin-RING-ligase-5) to ubiquitylate NOXA via a novel K11, but not K48, 
linkage for targeted proteasomal degradation. CRL5 inactivation or forced 
expression of K11R ubiquitin mutant caused NOXA accumulation to induce 
apoptosis, which is rescued by NOXA knockdown. Notably, NOXA knockdown rescues 
the UBE2F silencing effect, indicating a causal role of NOXA in this process. In 
lung cancer tissues, high levels of UBE2F and CUL5 correlate with a low level of 
NOXA and poor patient survival.Conclusions: By ubiquitylating and degrading NOXA 
through activating CRL5, UBE2F selectively promotes lung cancer cell survival 
and could, therefore, serve as a novel cancer target. Clin Cancer Res; 23(4); 
1104-16. ©2016 AACR.