The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1

Xu, Xin; Han, Kai; Tang, Xiaowen; Zeng, Yuanying; Lin, Xu; Zhao, Yun; Zhang, Zubin; Cao, Biyin; Wu, Depei; Mao, Xinliang

doi:10.1074/jbc.m115.701979

Cited by 50 publications

(90 citation statements)

References 22 publications

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“…As shown in Figure 1E, all cell lines examined displayed a high level of RNF6, in contrast, it was unable to be detected in a normal breast tissue cell line MCF-10A. This finding was consistent to previous reports that RNF6 was dysregulated in cancers such as leukemia [6] and prostate cancers [5]. Of interest, among these cell lines tested, T47D and MCF-7 are highly expressing estrogen receptor and MDA-MB-231 and MDA-MB-453 express relatively low levels of ER [7].…”

Section: Resultssupporting

confidence: 91%

“…RNF6 as an oncogene promotes prostate cancer progression [5]. Recently, we found that RNF6 is highly expressed in leukemia, myeloma, and other hematological malignancies and contributes to leukemia cell proliferation in vitro and in vivo [6]. The present study showed that RNF6 is dysregulated in more than 70% of breast cancer tissues and it is negatively associated with the survival period of breast cancer patients, which suggesting RNF6 is probably associated with its specific pathophysiological activity.…”

Section: Discussionsupporting

confidence: 50%

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Ring finger protein 6 promotes breast cancer cell proliferation by stabilizing estrogen receptor alpha

Zeng

Wang

et al. 2017

Oncotarget

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Ring finger protein 6 (RNF6) is a key oncogene in both prostate cancer and leukemia, but its role is elusive in breast cancer. In the present study, we found that RNF6 was overexpressed in more than 70% of breast cancer tissues and it was associated with overall survival. RNF6 increased breast cancer cell proliferation, migration and reduced cell sensitivity to doxorubicin. Further studies showed that RNF6 was closely associated with increased expression of estrogen receptor, a critical factor in the development of breast cancers. RNF6 was found to induce ERα expression and increased its stability. In doxorubicin-resistant breast cancer cells, RNF6 was found to be elevated in association with increased ERα and anti-apoptotic Bcl-xL, but not pro-apoptotic Bim-1. In consistence with this finding, overexpression of ERα led to increased Bcl-xL but had no effects on Bim-1. Therefore, this study demonstrated that there exists an RNF6/ERα/Bcl-xL axle in breast cancer which promotes cancer cell proliferation and survival. Targeting the RNF6/ERα/Bcl-xL axle could be a promising strategy in the treatment of breast cancer.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 50%

Ring finger protein 6 promotes breast cancer cell proliferation by stabilizing estrogen receptor alpha

Zeng

Wang

et al. 2017

Oncotarget

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“…Myeloma xenografts with human MM cell line LP1 were established in immunodeficient nude mice, followed by intratumoral transfection of UBE2O plasmids delivered by in vivo jetPEI as demonstrated previously [17, 23, 24]. The results showed that re-expression of UBE2O decreased myeloma tumor growth (Fig.…”

Section: Resultsmentioning

confidence: 61%

The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis

Zhang

et al. 2017

J Hematol Oncol

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BackgroundUBE2O is proposed as a ubiquitin-conjugating enzyme, but its function was largely unknown.MethodsMass spectrometry was applied to identify c-Maf ubiquitination-associated proteins. Immunoprecipitation was applied for c-Maf and UBE2O interaction. Immunoblotting was used for Maf protein stability. Luciferase assay was used for c-Maf transcriptional activity. Lentiviral infections were applied for UBE2O function in multiple myeloma (MM) cells. Flow cytometry and nude mice xenografts were applied for MM cell apoptosis and tumor growth assay, respectively.ResultsUBE2O was found to interact with c-Maf, a critical transcription factor in MM, by the affinity purification/tandem mass spectrometry assay and co-immunoprecipitation assays. Subsequent studies showed that UBE2O mediated c-Maf polyubiquitination and degradation. Moreover, UBE2O downregulated the transcriptional activity of c-Maf and the expression of cyclin D2, a typical gene modulated by c-Maf. DNA microarray revealed that UBE2O was expressed in normal bone marrow cells but downregulated in MGUS, smoldering MM and MM cells, which was confirmed by RT-PCR in primary MM cells, suggesting its potential role in myeloma pathophysiology. When UBE2O was restored, c-Maf protein in MM cells was significantly decreased and MM cells underwent apoptosis. Furthermore, the human MM xenograft in nude mice showed that re-expression of UBE2O delayed the growth of myeloma xenografts in nude mice in association with c-Maf downregulation and activation of the apoptotic pathway.ConclusionsUBE2O mediates c-Maf polyubiquitination and degradation, induces MM cell apoptosis, and suppresses myeloma tumor growth, which provides a novel insight in understanding myelomagenesis and UBE2O biology.

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“…Luciferase activity was analyzed using Bright-Gloluciferase assay system as described previously [20]. …”

Section: Methodsmentioning

confidence: 99%

Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway

et al. 2016

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Interferon-stimulated gene 15 (ISG15) is an important cytokine that has been reported in carcinogenesis. However, we found that ISG15 and de-ISGylase USP18 were induced by several anti-cancer agents, which was confirmed by both RT-PCR and immunoblotting assays. Further studies demonstrated that ectopic ISG15 and USP18 inhibited proliferation of myeloma, leukemia and cervical cancer cells. More importantly, ISG15 and USP18 induced cancer cell apoptosis. This finding was confirmed in a cervical xenograft model in which cervical cancer growth was suppressed by lentiviral ISG15. In the mechanistic study, ISG15 was found to disrupt the NF-κB signaling pathway by downregulating the expression of IKKβ and p65, phosphorylation of p65 and IκBα. Consistent with this finding, ISG15 suppressed the expression of NF-κB recognition element-driving luciferase and decreased the transcription of XIAP and Mcl-1, two typical genes regulated by NF-κB. Therefore, the present study demonstrated that ISG15 induces cancer cell apoptosis by disrupting the NF-κB signaling pathway. This study highlighted a novel role of ISG15 in tumor suppression.

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The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1

Cited by 50 publications

References 22 publications

Ring finger protein 6 promotes breast cancer cell proliferation by stabilizing estrogen receptor alpha

Ring finger protein 6 promotes breast cancer cell proliferation by stabilizing estrogen receptor alpha

The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis

Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway

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