The Nuclear Import of Oncoprotein Hepatitis B X-interacting Protein Depends on Interacting with c-Fos and Phosphorylation of Both Proteins in Breast Cancer Cells

Zhang, Yingyi; Zhao, Yu; Li, Hang; Li, Yinghui; Cai, Xiaoli; Shen, Yun; Shi, Hui; Li, Leilei; Liu, Qian; Zhang, Xiaodong; Ye, Lihong

doi:10.1074/jbc.m113.458638

Cited by 30 publications

(21 citation statements)

References 47 publications

(34 reference statements)

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“…It has been reported that HBXIP is required for mTORC1 activation by amino acid in cell growth (14). Importantly, our study has revealed that HBXIP requires the interaction with c-Fos and phosphorylation of both proteins for nuclear import (15) and acts as a coactivator for transcription factors including CREB, TFIID, Sp1, E2F1, and STAT4 in the development of breast cancer (15)(16)(17)(18). Therefore, we supposed that HBXIP might play a crucial role in abnormal lipid metabolism of breast cancer.…”

Section: Introductionmentioning

confidence: 80%

Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade

Zhao

Zhang

et al. 2016

Cancer Research

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Abnormal lipid metabolism is a hallmark of tumorigenesis. Accumulating evidence demonstrates that fatty acid synthase (FAS, FASN) is a metabolic oncogene that supports the growth and survival of tumor cells and is highly expressed in many cancers. Here, we report that the oncoprotein, hepatitis B Xinteracting protein (HBXIP, LAMTOR5) contributes to abnormal lipid metabolism. We show that high expression of HBXIP in 236 breast cancer patients was significantly associated with decreased overall survival and progression-free survival. Interestingly, the expression of HBXIP was positively related to that of FAS in clinical breast cancer tissues, and HBXIP overexpression in breast cancer cells resulted in FAS upregulation. Mechanistically, HBXIP upregulated SREBP-1c (SREBF1), which activates the transcription of FAS, by directly interacting with and coactivating nuclear receptor (NR) liver X receptors (LXR). Physiologically, LXRs are activated via a coactivator containing NR motif in a liganddependent manner. However, in breast cancer cells, HBXIP containing the corepressor/nuclear receptor motif with special flanking sequence could coactivate LXRs independent of ligand. Moreover, overexpressed SREBP-1c was able to activate the transcription of HBXIP, forming a positive-feedback loop. Functionally, HBXIP enhanced lipogenesis, resulting in the growth of breast cancer cells in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP contributes to the abnormal lipid metabolism in breast cancer through LXRs/SREBP-1c/FAS signaling, providing new insights into the mechanisms by which cancer cells reprogram lipid metabolism in their favor.

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Section: Introductionmentioning

confidence: 80%

Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade

Zhao

Zhang

et al. 2016

Cancer Research

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“…For example, c-Fos interacts with CBFA1 to activate the collagenase-3 promoter (39), and the nuclear import of HBXIP (hepatitis B X-interacting protein) relies on the interaction between HBXIP and c-Fos and the phosphorylation of these two proteins in breast cancer cells (40). However, the interaction between c-Fos and these proteins, including IL1R2, and their involvement in transcriptional activation, remain obscure.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 Receptor Type 2 Acts with c-Fos to Enhance the Expression of Interleukin-6 and Vascular Endothelial Growth Factor A in Colon Cancer Cells and Induce Angiogenesis

Mar

Chu

Lee

et al. 2015

Journal of Biological Chemistry

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Background: Enhanced IL1R2 expression has frequently been observed in tumors, but its function is unclear. Results: Intracellular IL1R2 transcriptionally activates IL-6 and VEGF-A by complexing with c-Fos and promotes the angiogenesis of colon cancer cells. Conclusion: IL1R2 functions as a transcriptional coactivator to enhance the expression of angiogenic factors. Significance: IL1R2 activates angiogenic factors and hence may serve as a clinical marker for prognosis or treatment.

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“…HBXIP functions as an oncogenic transcriptional co-activator in breast cancer (19,35). Either HBXIP or c-Myc contains a leucine-zipper domain (5,15).…”

Section: Resultsmentioning

confidence: 99%

“…The plasmids, such as pCMV-Tag2B, pCMV-HBXIP, pcDNA3.1, pcDNA-HBXIP, pGEX-4T1, pGEX-HBXIP, and pCMV-HBXIP-LZM, were used in our previous studies (16,34,35). The E-box reporter was constructed by inserting 6Â E-box into the pGL3-Basic vector (36).…”

Section: Constructsmentioning

confidence: 99%

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HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc

et al. 2016

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c-Myc is regarded as a transcription factor, but the basis for its function remains unclear. Here, we define a long noncoding RNA (lncRNA)/protein complex that mediates the transcriptional activation by c-Myc in breast cancer cells. Among 388 c-Myc target genes in human MCF-7 breast cancer cells, we found that their promoters could be occupied by the oncoprotein HBXIP. We confirmed that the HBXIP expression correlated with expression of the c-Myc target genes cyclin A, eIF4E, and LDHA. RNAi-mediated silencing of HBXIP abolished c-Mycmediated upregulation of these target genes. Mechanistically, HBXIP interacted directly with c-Myc through the leucine zippers and recruited the lncRNA Hotair along with the histone demethylase LSD1, for which Hotair serves as a scaffold. Silencing of HBXIP, Hotair, or LSD1 was sufficient to block c-Myc-enhanced cancer cell growth in vitro and in vivo. Taken together, our results support a model in which the HBXIP/ Hotair/LSD1 complex serves as a critical effector of c-Myc in activating transcription of its target genes, illuminating longstanding questions on how c-Myc drives carcinogenesis. Cancer Res; 76(2); 293-304. Ó2015 AACR.

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The Nuclear Import of Oncoprotein Hepatitis B X-interacting Protein Depends on Interacting with c-Fos and Phosphorylation of Both Proteins in Breast Cancer Cells

Cited by 30 publications

References 47 publications

Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade

Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade

Interleukin-1 Receptor Type 2 Acts with c-Fos to Enhance the Expression of Interleukin-6 and Vascular Endothelial Growth Factor A in Colon Cancer Cells and Induce Angiogenesis

HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc

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