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The oncoprotein HBXIP activates transcriptional coregulatory protein LMO4 via Sp1 to promote proliferation of breast cancer cells.

ABSTRACT: Hepatitis B X-interacting protein (HBXIP) is an important oncoprotein that plays critical role in the development of cancer. In this study, we report that HBXIP activates LIM-only protein 4 (LMO4), a transcriptional coregulatory protein, in promotion of cell proliferation. We observed that the messenger RNA (mRNA) expression levels of HBXIP were positively associated with those of LMO4 in clinical breast cancer tissues. We further identified that HBXIP upregulated LMO4 at the levels of promoter, mRNA and protein in MCF-7 and LM-MCF-7 breast cancer cell lines. The expression of cyclin D1 and cyclin E, downstream effectors of LMO4, could be upregulated by HBXIP through LMO4. Then, chromatin immunoprecipitation (ChIP) assay revealed that HBXIP was able to interact with the promoter region of LMO4. Electrophoretic mobility shift assay showed that HBXIP occupied the -237/-206 region of LMO4 promoter containing Sp1 binding element. The mutant of Sp1 binding site in the LMO4 promoter impeded the interaction of HBXIP with the promoter. Co-immunoprecipitation, ChIP and luciferase reporter gene assays showed that HBXIP activated LMO4 promoter through binding to Sp1. In function, flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays and animal transplantation assays demonstrated that HBXIP-enhanced cell proliferation of breast cancer through upregulating LMO4 in vitro and in vivo. Thus, we concluded that oncoprotein HBXIP is able to activate the transcriptional coregulatory protein LMO4 through transcription factor Sp1 in promotion of proliferation of breast cancer cells. HBXIP may serve as a driver gene to activate transcription in the development of cancer.

SUBMITTER: Yue L

PROVIDER: S-EPMC3616668 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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The oncoprotein HBXIP activates transcriptional coregulatory protein LMO4 via Sp1 to promote proliferation of breast cancer cells.

Yue Lin L Li Leilei L Liu Fangfang F Hu Nan N Zhang Weiying W Bai Xiao X Li Yinghui Y Zhang Yingyi Y Fu Li L Zhang Xiaodong X Ye Lihong L

Carcinogenesis 20130105 4

Hepatitis B X-interacting protein (HBXIP) is an important oncoprotein that plays critical role in the development of cancer. In this study, we report that HBXIP activates LIM-only protein 4 (LMO4), a transcriptional coregulatory protein, in promotion of cell proliferation. We observed that the messenger RNA (mRNA) expression levels of HBXIP were positively associated with those of LMO4 in clinical breast cancer tissues. We further identified that HBXIP upregulated LMO4 at the levels of promoter, ...[more]

PMID: 23291272

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Project description:BackgroundResistance to tamoxifen (TAM) frequently occurs in the treatment of estrogen receptor positive (ER+) breast cancer. Accumulating evidences indicate that transcription factor HOXB13 is of great significance in TAM resistance. However, the regulation of HOXB13 in TAM-resistant breast cancer remains largely unexplored. Here, we were interested in the potential effect of HBXIP, an oncoprotein involved in the acceleration of cancer progression, on the modulation of HOXB13 in TAM resistance of breast cancer.MethodsThe Kaplan-Meier plotter cancer database and GEO dataset were used to analyze the association between HBXIP expression and relapse-free survival. The correlation of HBXIP and HOXB13 in ER+ breast cancer was assessed by human tissue microarray. Immunoblotting analysis, qRT-PCR assay, immunofluorescence staining, Co-IP assay, ChIP assay, luciferase reporter gene assay, cell viability assay, and colony formation assay were performed to explore the possible molecular mechanism by which HBXIP modulates HOXB13. Cell viability assay, xenograft assay, and immunohistochemistry staining analysis were utilized to evaluate the effect of the HBXIP/HOXB13 axis on the facilitation of TAM resistance in vitro and in vivo.ResultsThe analysis of the Kaplan-Meier plotter and the GEO dataset showed that mono-TAM-treated breast cancer patients with higher HBXIP expression levels had shorter relapse-free survivals than patients with lower HBXIP expression levels. Overexpression of HBXIP induced TAM resistance in ER+ breast cancer cells. The tissue microarray analysis revealed a positive association between the expression levels of HBXIP and HOXB13 in ER+ breast cancer patients. HBXIP elevated HOXB13 protein level in breast cancer cells. Mechanistically, HBXIP prevented chaperone-mediated autophagy (CMA)-dependent degradation of HOXB13 via enhancement of HOXB13 acetylation at the lysine 277 residue, causing the accumulation of HOXB13. Moreover, HBXIP was able to act as a co-activator of HOXB13 to stimulate interleukin (IL)-6 transcription in the promotion of TAM resistance. Interestingly, aspirin (ASA) suppressed the HBXIP/HOXB13 axis by decreasing HBXIP expression, overcoming TAM resistance in vitro and in vivo.ConclusionsOur study highlights that HBXIP enhances HOXB13 acetylation to prevent HOXB13 degradation and co-activates HOXB13 in the promotion of TAM resistance of breast cancer. Therapeutically, ASA can serve as a potential candidate for reversing TAM resistance by inhibiting HBXIP expression.

Project description:ObjectiveThe oncoprotein, hepatitis B X-interacting protein (HBXIP), has been reported to play an important role in human malignancies. However, its functions in non-small cell lung cancer (NSCLC) are poorly understood. The goal of the present study was to identify the role of HBXIP in the regulation of NSCLC development.MethodsThe level of HBXIP expression in NSCLC tissue was assessed by immunohistochemical and Western blot analyses, and its relationships with clinicopathological features and outcomes were statistically evaluated. The effects of HBXIP on NSCLC cell progression were assessed through cell viability, colony formation, and flow cytometry analyses in vitro. The mechanism by which HBXIP regulated the MAPK pathway was studied by Western blot, immunofluorescence, and immunoprecipitation assays. In addition, in vivo experiments were performed to evaluate the progression of NSCLC and ERK signaling pathway activation after HBXIP knockdown.ResultsHBXIP was overexpressed in human NSCLC and was correlated with the invasiveness of NSCLC. The high expression of HBXIP in NSCLC was significantly correlated with gender (P = 0.033), N stage (P = 0.002), and tumor-node-metastasis stage (P = 0.008). In vitro experiments using an NSCLC cell line revealed that HBXIP knockdown resulted in the suppression of cell proliferation and colony formation, which was consistent with the enhanced cell cycle arrest in G1 phase. The results of a mechanistic investigation suggested that binding of HBXIP to MEK1 protein promoted MAPK/ERK signaling pathway activation in NSCLC by preventing the proteasome-mediated degradation of MEK1. In addition, the results obtained using in vivo subcutaneous tumor xenografts confirmed that HBXIP deficiency decreased MEK1 protein levels and NSCLC tumor growth.ConclusionsTaken together, our results showed that the HBXIP-MEK interaction promoted oncogenesis via the MAPK/ERK pathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.

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The oncoprotein HBXIP activates transcriptional coregulatory protein LMO4 via Sp1 to promote proliferation of breast cancer cells.

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The oncoprotein HBXIP activates transcriptional coregulatory protein LMO4 via Sp1 to promote proliferation of breast cancer cells.

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