Induction of zinc finger protein RNF6 auto-ubiquitination for the treatment of myeloma and chronic myeloid leukemia

Zhuang, Haixia; Ren, Ying; Mao, Chenyu; Zhong, Yueya; Zhang, Zubin; Cao, Biyin; Zhang, Yuming; Huang, Jiefeng; Xu, Guoqiang; Huang, Zhongcheng; Xu, Yujia; Mao, Xinliang

doi:10.1016/j.jbc.2022.102314

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…Although a recent study reported that RNF6 is highly expressed in NSCLC tissues based on a database at Kaplan-Meier Plotter ( http://kmplot.com/ ) but the plots could not be reproduced 28 . In the same study, the RING domain-deleting RNF6 remains the same size as the wild type in the IB assay 28 , this result is impossible because the RING domain is composed of 44 amino acids and the molecular weight is around 5 kDa, which could be clearly distinguished 9 , 29 .In the present study, we solidified the conclusion that PBX1/RNF6 was downregulated in NSCLC tissues and suppress cell proliferation. However, the molecular mechanism underlying that RNF6 inhibits NSCLC should be further investigated.…”

Section: Discussionsupporting

confidence: 60%

TRIM26 promotes non-small cell lung cancer survival by inducing PBX1 degradation

Sun¹,

Lin²,

Zhou³

et al. 2023

Int. J. Biol. Sci.

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The transcription factor PBX1 is regarded as an oncogene in various cancers, but its role in non-small cell lung cancer (NSCLC) and the detailed mechanism is not known. In the present study, we found that PBX1 is downregulated in NSCLC tissues and inhibits NSCLC cell proliferation and migration. Subsequently, we performed an affinity purification-coupled tandem mass spectrometry (MS/MS) and found the ubiquitin ligase TRIM26 in the PBX1 immunoprecipitates. Moreover, TRIM26 binds to and mediates PBX1 for K48-linked polyubiquitination and proteasomal degradation. Noticeably, TRIM26 activity depends on its C-terminal RING domain when it is deleted TRIM26 loses its function towards PBX1. TRIM26 further inhibits PBX1 transcriptional activity and downregulates the PBX1 downstream genes, such as RNF6. Moreover, we found that overexpression of TRIM26 significantly promotes NSCLC proliferation, colony formation, and migration in contradiction to PBX1. TRIM26 is highly expressed in NSCLC tissues and predicts poor prognosis. Lastly, the growth NSCLC xenografts is promoted by overexpression of TRIM26 but is suppressed by TRIM26 knockout. In conclusion, TRIM26 is a ubiquitin ligase of PBX1 and it promotes while PBX1 inhibits NSCLC tumor growth. TRIM26 might be a novel therapeutic target for the treatment of NSCLC.

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Section: Discussionsupporting

confidence: 60%

TRIM26 promotes non-small cell lung cancer survival by inducing PBX1 degradation

Sun¹,

Lin²,

Zhou³

et al. 2023

Int. J. Biol. Sci.

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“…In the present study, by utilizing combined techniques and strategies, including the deubiquitinase library screen, the affinity‐purification coupled tandem MS and various biochemical assays, we identified that USP7 is a putative deubiquitinase of c‐Abl, which helps to understand the underlying mechanism in c‐Abl modulation by ubiquitination. USP7, or HAUSP, has been shown to modulate a variety of substrates, including both oncoproteins (such as RNF6) 12 and tumour suppressor proteins (such as PTEN). 13 However, different from its action on other substrates, USP7 stabilizes c‐Abl at both unphosphorylated and phosphorylated forms.…”

Section: Discussionmentioning

confidence: 99%

“…HEK293T cells expressing a HA‐c‐Abl plasmid were subjected to protein purification as described previously 12 and the extracted proteins were then incubated with HA‐tagged beads for 16 h at 4°C for immunoprecipitation (IP) assay. The prepared protein samples were Coomassie blue staining (Beyotime) before the bands were prepared for MS/MS assay 12,16 …”

Section: Methodsmentioning

confidence: 99%

“…The prepared protein samples were Coomassie blue staining (Beyotime) before the bands were prepared for MS/MS assay. 12 , 16 …”

Section: Methodsmentioning

confidence: 99%

“… 11 However, there are no proven Dubs reported for c‐Abl ubiquitination and stability. USP7, also known as herpesvirus‐associated ubiquitin‐specific protease (HAUSP) or ubiquitin carboxyl‐terminal hydrolase 7, is one of the most studied deubiquitinases, and a myriad of substrate proteins have been assigned to USP7, including PTEN, P53, RNF6, 12 and BCR‐ABL, c‐Myc and many others. 13 In the present study, we found USP7 as a deubiquitinase that can prevent c‐Abl from K48‐linked polyubiquitination and proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%

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USP7 promotes non‐small‐cell lung cancer cell glycolysis and survival by stabilizing and activating c‐Abl

He,

Jiang,

Zhong

et al. 2023

Clinical & Translational Med

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BackgroundAbelson tyrosine kinase (c‐Abl) is frequently mutated and highly expressed, and promotes non‐small‐cell lung cancer (NSCLC) survival, metastasis and tumorigenesis. c‐Abl could also be modified through ubiquitination, but the underlying mechanism is not well understood.MethodsMass spectrometry assays were performed to search c‐Abl deubiquitination enzymes. The molecular mechanism was determined using Co‐IP assays, pull‐down assays, Western blotting upon gene knockdown or overexpression. Cell lines and animal models were used to investigate the role of c‐Abl and USP7 in NSCLC. EdU staining assay and Transwell assay were performed to evaluate the proliferation and migration ability of NSCLC cells, respectively.ResultsUbiquitin‐specific protease 7 (USP7) is found to upregulate c‐Abl via the deubiquitinase screen. USP7 interacts with c‐Abl and decreases its K48‐linked polyubiquitination, thereby increasing the stability of c‐Abl. In addition to the wild‐type one, c‐Abl mutants can also be deubiquitinated and stabilized by USP7. Moreover, USP7 promotes c‐Abl accumulation in cytoplasm by increasing its binding to 14‐3‐3α/β and activates the oncogenic c‐Abl signalling pathway. Furthermore, the USP7/c‐Abl axis promotes NSCLC cell glycolysis by direct phosphorylating and stabilizing hexokinase‐2 (HK2). Knockdown of USP7 or c‐Abl suppresses NSCLC cell glycolysis and reduces lactate production. Further studies revealed that overexpression of USP7 facilitates NSCLC cell growth and metastasis as well as xenograft growth in nude mice, while these activities are suppressed with USP7 or c‐Abl being knocked down.ConclusionsUSP7 is a deubiquitinase of c‐Abl and upregulates its oncogenic activity. USP7 promotes NSCLC cell metabolism by activating c‐Abl and HK2. Targeting the USP7/c‐Abl/HK2 axis might be a potential strategy to the precision therapy of NSCLC.

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Fundamental concepts of protein therapeutics and spacing in oncology: an updated comprehensive review

et al. 2023

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Induction of zinc finger protein RNF6 auto-ubiquitination for the treatment of myeloma and chronic myeloid leukemia

Cited by 8 publications

References 27 publications

TRIM26 promotes non-small cell lung cancer survival by inducing PBX1 degradation

TRIM26 promotes non-small cell lung cancer survival by inducing PBX1 degradation

USP7 promotes non‐small‐cell lung cancer cell glycolysis and survival by stabilizing and activating c‐Abl

Fundamental concepts of protein therapeutics and spacing in oncology: an updated comprehensive review

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