Induction of NEDD8-conjugating enzyme E2 UBE2F by platinum protects lung cancer cells from apoptosis and confers to platinum-insensitivity

Abstract

Platinum is a widely used first-line chemotherapy in treating non-small cell lung cancer of adenocarcinoma. Unfortunately, platinum resistance leads to relapse and therapeutic failure, enabling the development of platinum-sensitization strategies to be of great clinical significance. Here, we report that the upregulation of the NEDD8-conjugating enzyme UBE2F is an important way for lung cancer cells to escape platinum-induced cell apoptosis, which confers to insensitivity to platinum-based chemotherapy. Mechanistically, platinum treatment impairs the complex formation for proteasome-mediated UBE2F degradation, evidenced by the weaker association between UBE2F and Ring-box protein 1 (RBX1), an essential component of Cullin-Ring E3 ligases (CRLs), thus leading to the accumulation of UBE2F. The accumulated UBE2F promotes the neddylation levels and activity of Cullin5, in accord with the lower expression of pro-apoptotic protein NOXA, a well-known substrate of Cullin-Ring E3 ligase 5 (CRL5). Additionally, knockout of UBE2F significantly sensitizes lung cancer cells to platinum treatment by enhancing the protein levels of NOXA and subsequently promoting cell apoptosis. Our observations uncover a previously unknown regulatory mechanism of UBE2F stability upon platinum chemotherapy and suggest that UBE2F might be a novel therapy target for sensitizing lung cancer cells to platinum-based chemotherapy.

A polydopamine nanomedicine used in photothermal therapy for liver cancer knocks down the anti-cancer target NEDD8-E3 ligase ROC1 (RBX1)

“…9 A, the genetic nanomedicine significantly inhibited the Neddylation modification of Cul1 but had little influence on the Neddylation modification of Cul5 in Huh7 cells. This outcome was a result of the role of Cul1 as a ROC1 substrate (RBX1, E3), while Cul5 is a substrate of ROC2 (RBX2/SAG, E3) [ 41 ]. Moreover, ROC1 knockdown lead to upregulated ATF4 expression, which can promote the apoptosis of tumor cells [ 42 ].…”

Ubiquitin Proteasome Pathway Transcriptome in Epithelial Ovarian Cancer

“…Expression of the genes encoding the NEDD8 conjugases, UBE2M and UBE2K, was significantly greater in HGSOC than in LMP (F = 5.25, p < 0.05; F = 22.81, p < 0.0001). UBE2M is a NEDD8-conjugating enzyme that facilitates neddylation and activation of Cullin Ring 1–4 ligases, while UBE2F facilitates the neddylation of Cullin Ring 5 ligases [ 59 , 60 , 61 ]. UBE2F has been promoted as a target to enhance platinum sensitivity in chemotherapy of lung cancer cells [ 59 ].…”

E3 ubiquitin ligase RBX1 drives the metastasis of triple negative breast cancer through a FBXO45-TWIST1-dependent degradation mechanism

“…RBX1 is overexpressed in many primary tumours, including liver cancer, non-musculoinvasive transitional cell carcinoma of the bladder (NMIBC), and lung cancer [32][33][34][35][36]. Several studies have shown that RBX1 is participated in different aspects of the cancer biology, and lots of RBX1 molecular functions are in accordance with its function in cancer [37][38][39]. Nonetheless, there exist no information on the RBX1 molecular mechanisms and its concrete role in TNBC.…”