Dataset Information

Ubiquitin conjugating enzyme E2 L3 promoted tumor growth of NSCLC through accelerating p27kip1 ubiquitination and degradation.

ABSTRACT: The molecular pathogenesis of human lung cancer has not been completely clarified. Here, we reported that UBE2L3, a member of the ubiquitin-conjugating enzymes (E2s), were overexpressed in non-small-cell lung cancer (NSCLC) tissues compared with the non-tumor tissues. High expression of UBE2L3 was correlated with advanced tumor stage and adverse outcomes. Knockdown of UBE2L3 inhibited NSCLC cell growth while ectopic expression of UBE2L3 promoted NSCLC cell growth in a cell cycle dependent manner. The results of subcutaneous tumor xenograft studies revealed that knockdown of UBE2L3 attenuated the in vivo tumor growth. Mechanistically, we observed that UBE2L3 could interact with F-box protein Skp2, a member of the SCF (Skp2) ubiquitin ligase complex, and thus promoted the ubiquitination and proteasomal degradation of p27kip1. Furthermore, NSCLC cases with high level of UBE2L3 and low level of p27kip1 had worst prognosis, suggesting that combination of UBE2L3 and p27kip1 is a more powerful prognostic marker for NSCLC patients. Taken together, the current study presented a novel marker for predicting prognosis and a potential therapeutic target for NSCLC patients.

SUBMITTER: Ma X

PROVIDER: S-EPMC5663587 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Ubiquitin conjugating enzyme E2 L3 promoted tumor growth of NSCLC through accelerating p27kip1 ubiquitination and degradation.

Ma Xingjie X Zhao Junjie J Yang Fan F Liu Haitao H Qi Weibo W

Oncotarget 20170824 48

The molecular pathogenesis of human lung cancer has not been completely clarified. Here, we reported that UBE2L3, a member of the ubiquitin-conjugating enzymes (E2s), were overexpressed in non-small-cell lung cancer (NSCLC) tissues compared with the non-tumor tissues. High expression of UBE2L3 was correlated with advanced tumor stage and adverse outcomes. Knockdown of UBE2L3 inhibited NSCLC cell growth while ectopic expression of UBE2L3 promoted NSCLC cell growth in a cell cycle dependent manner ...[more]

PMID: 29137415

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Project description:The Androgen Receptor (AR) is a pivotal protein in human physiology, exerting significant influence on both male and female physiology (PMID: 18434134, 25905231). Functioning as a nuclear transcription factor, AR binds to testosterone, translocates to the nucleus, and subsequently regulates the expression of numerous genes, impacting vital cellular processes such as cell proliferation, differentiation, and apoptosis (PMID: 4810760, 25237629). The prominent role of AR in human physiology is particularly notable in the context of prostate cancer initiation, where aberrant AR signaling has been identified as a key driver in tumorigenesis (PMID: 4810760, 27057074, 37429011). However, despite the considerable success of the current anti-androgen therapeutic approach, it faces the formidable challenge of drug resistance, significantly limiting the clinical outcome for patients and necessitating the urgent development of new therapeutic approaches to overcome resistance (PMID: 26563462, 24881730, 31363002, 35582713). Notably, one key feature of antiandrogen resistance is the sustained or enhanced AR signaling observed in many resistant tumors (PMID: 26563462, 34449248, 23580326), although the underlying molecular mechanisms remain largely unclear. Protein degradation, with ubiquitination at its core, plays a critical role in cell functionality, ensuring the elimination of redundant and harmful proteins (PMID: 16738015, 33634825). This intricate process involves the attachment of small proteins called ubiquitin to target proteins, marking them for degradation. Dysregulation of ubiquitination can lead to the accumulation of oncogenic proteins, contributing to tumorigenesis and therapy resistance in various cancers (PMID: 32296023, 33004065). The degradation of proteins is a complex process that involves the coordination of E1, E2 and E3 enzymes, with E3 enzymes binding to the target protein (PMID: 21111229, 20930542). Logically, research has focused on finding E3s targeting AR for degradation but has overlooked the role that E2s play in the ubiquitination process. In recent years, E2s have been shown to dictate the how and where ubiquitin gets attached in the target protein, dictating the fate of the protein (PMID: 27002219, 19851334). Therefore, finding the E2 involved in the degradation of AR can prove to be essential. In this study, we conducted an in vivo library screening approach and identified UBE2J1 as the bona fide E2 ubiquitin conjugating enzyme for AR ubiquitination. Our results demonstrated that the frequent loss of UBE2J1 in prostate cancer leads to dysregulated and impaired AR ubiquitination and degradation. Consequently, this promotes the accumulation of AR proteins and confers resistance to antiandrogen treatment in UBE2J1-deficient prostate cancer cells. To address this, we developed an innovative ubiquitination-based AR degrader that effectively restores AR ubiquitination, thereby resensitizing prostate cancer cells to antiandrogen therapy. These findings not only unveil the pivotal role of UBE2J1 as the crucial E2 ubiquitin conjugating enzyme for AR degradation but also shed light on a novel mechanism through which advanced prostate cancer cells upregulate AR protein levels, thereby acquiring resistance to existing antiandrogen therapy. These novel insights hold the potential to inform the development of more effective therapeutic strategies against advanced prostate cancers.

Dataset Information

Ubiquitin conjugating enzyme E2 L3 promoted tumor growth of NSCLC through accelerating p27kip1 ubiquitination and degradation.

Publications

Ubiquitin conjugating enzyme E2 L3 promoted tumor growth of NSCLC through accelerating p27kip1 ubiquitination and degradation.

Similar Datasets

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