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ZHX2 mediates proteasome inhibitor resistance via regulating nuclear translocation of NF-?B in multiple myeloma.

ABSTRACT: BACKGROUND:Multiple myeloma (MM) is an incurable hematological malignancy. Although proteasome inhibitors and immunomodulators have significantly improved patient outcomes, some patients respond poorly to treatment and almost all patients will relapse. Mechanisms of proteasome inhibitor resistance in multiple myeloma have not been fully elucidated. ZHX2 is a transcription regulator degraded via proteasome and presents both oncogenic or tumor suppressive effect in different cancers, however, it is still unknown that the role of ZHX2 in myeloma. In this study, we aim to demonstrate the effect and mechanism of ZHX2 on proteasome inhibitor resistance in MM. METHODS:GSE24080 gene expression profile datasets from Gene Expression Omnibus (GEO) were analyzed to evaluate the relationship between ZHX2 expression level and survival in MM. Expression of ZHX2 in human MM cell lines at baseline and after bortezomib (BTZ) treatment was determined by Western blotting (WB). The proliferation and apoptosis rate of MM cells treated with BTZ after the knockdown of ZHX2 were analyzed by flow cytometry. Nuclear translocation of NF-?B after the knockdown of ZHX2 was evaluated by WB and immunofluorescence, and the expression of NF-?B target genes was measured by real-time quantitative PCR. Co-immunoprecipitation (Co-IP) and WB were used to detect the interaction of ZHX2 with NF-?B. RESULTS:We found that higher ZHX2 expression was correlated with poorer clinical outcomes of patients. In addition, ZHX2 expression was relatively higher in RPMI-8226 and MM.1S cell lines and the level of ZHX2 protein was upregulated after BTZ treatment. Knockdown of ZHX2 significantly enhanced the sensitivity of MM cells to BTZ, inhibited nuclear translocation of NF-?B, and reduced mRNA expression of NF-?B target genes. It was also revealed that ZHX2 directly binds to NF-?B. CONCLUSION:Our study showed that ZHX2 can promote proteasome inhibitor resistance in MM cells by regulating the nuclear translocation of NF-?B.

SUBMITTER: Jiang J

PROVIDER: S-EPMC7541163 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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ZHX2 mediates proteasome inhibitor resistance via regulating nuclear translocation of NF-κB in multiple myeloma.

Jiang Jifeng J Sun Yifeng Y Xu Jiadai J Xu Tianhong T Xu Zhao Z Liu Peng P

Cancer medicine 20200811 19

<h4>Background</h4>Multiple myeloma (MM) is an incurable hematological malignancy. Although proteasome inhibitors and immunomodulators have significantly improved patient outcomes, some patients respond poorly to treatment and almost all patients will relapse. Mechanisms of proteasome inhibitor resistance in multiple myeloma have not been fully elucidated. ZHX2 is a transcription regulator degraded via proteasome and presents both oncogenic or tumor suppressive effect in different cancers, howev ...[more]

PMID: 32780537

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Project description:BackgroundUbiquitin-fold modifier-1 (Ufm1) is a recently identified ubiquitin-like protein. We previously confirmed that Ufm1 expression was increased in diabetic mice. However, its role in the development of diabetes remains undefined.MethodsLentivirus-mediated gene knockdown and overexpression techniques were used to observe the effect of Ufm1 on the expression of inflammatory factors, adhesion molecules and chemokines, as well as the transcriptional activity of nuclear factor kappa-B (NF-κB) in macrophages. Western blot and immunofluorescence analyses were used to analyse the mechanism by which Ufm1 affects the transcriptional activity of NF-κB. Finally, the effects of Ufm1 on inflammation and pancreatic, renal and myocardial damage were observed in db/db mice.ResultsKnockdown of Ufm1 by lentivirus shRNA targeting Ufm1 (Lv-shUfm1) led to decreased secretion of IL-6, IL-1β, ICAM-1, VCAM-1, MCP-1 and CXCL2 in RAW264.7 cells that were exposed to LPS and TNF-α, while lentiviral overexpression of Ufm1 (Lv-Ufm1) caused the opposite effect. Interestingly, further investigation indicated that Ufm1 induced NF-κB p65 nuclear translocation in RAW264.7 cells via increasing the ubiquitination and degradation of IκBα. In an in vivo experiment, pretreatment of db/db mice with Lv-shUfm1 reduced the mRNA levels of TNF-α, IL-6, IL-1β, ICAM-1, VCAM-1, MCP-1 and CXCL2 in resident peritoneal macrophages (RPMs) and decreased the plasma levels of TNF-α, IL-6, IL-1β, ICAM-1, VCAM-1, MCP-1 and CXCL2. Additionally, in Lv-Ufm1-treated mice, the inverse results were observed. Following treatment with Lv-shUfm1 and Lv-Ufm1, NF-κB p65 nuclear translocation in RPMs was decreased and increased, respectively. Importantly, we observed that Lv-shUfm1 injection led to a decrease in plasma glycaemia, a reduction in urinary albuminuria and cardiomyocyte hypertrophy and an improvement in the histopathological appearance of pancreatic, kidney and myocardial tissue. Pretreatment of the mice with Lv-shUfm1 inhibited macrophage infiltration in the pancreas, kidney and myocardial tissue.ConclusionOur data elucidate a new biological function of Ufm1 that mediates inflammatory responses. Ufm1-mediated p65 nuclear translocation occurs by modulating the ubiquitination and degradation of IκBα. Moreover, downregulating Ufm1 is an effective strategy to prevent the development of type 2 diabetes and its complications.

Dataset Information

ZHX2 mediates proteasome inhibitor resistance via regulating nuclear translocation of NF-?B in multiple myeloma.

Publications

ZHX2 mediates proteasome inhibitor resistance via regulating nuclear translocation of NF-κB in multiple myeloma.

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