The Oncoprotein HBXIP Uses Two Pathways to Up-regulate S100A4 in Promotion of Growth and Migration of Breast Cancer Cells

Liu, Shuangping; Li, Leilei; Zhang, Yingyi; Zhang, Yiwen; Zhao, Yu; You, Xiaona; Lin, Zhenhua; Zhang, Xiaodong; Ye, Lihong

doi:10.1074/jbc.m112.343947

Cited by 72 publications

(91 citation statements)

References 36 publications

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“…Moreover, we revealed that HBXIP was able to interact with the E-box in the promoters of c-Myc-induced genes. It further supports that HBXIP is a coactivator of transcriptional factor c-Myc, which is consistent with our reports that HBXIP is able to coactivate transcription factors, such as TF-IID, STAT3, SP1, CREB, and E2F1, in breast cancer cells (15)(16)(17)(18)(19)(20).…”

Section: Discussionsupporting

confidence: 93%

“…The electrophoresis mobility shift assay (EMSA) protocol was described in detail (16,17). Nuclear extracts were prepared with MCF-7 cells using the EpiQuik Nuclear Extraction Kit (Epigentek).…”

Section: Electrophoresis Mobility Shift Assaysmentioning

confidence: 99%

“…We have reported that expression of HBXIP is obviously enriched in breast cancer tissues. HBXIP acts as an oncogenic transcriptional coactivator of multiple transcription factors, such as TF-IID, STAT3, SP1, CREB, and E2F1, in the promotion of breast cancer growth and metastasis (15)(16)(17)(18)(19)(20). However, whether HBXIP serves as a coactivator of oncogenic transcriptional factor c-Myc in breast cancer remains poorly understood.…”

Section: Introductionmentioning

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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Section: Discussionsupporting

confidence: 93%

Section: Electrophoresis Mobility Shift Assaysmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Moreover, we found that HBXIP greatly upregulated FAS in breast cancer cells. Our recent work illustrated that the oncoprotein HBXIP as a transcription coactivator appeared to play a crucial role in promoting the development of breast cancer (16,(22)(23)(24). Accordingly, we hypothesized that the HBXIP might be involved in modulating FAS transcription.…”

Section: Discussionmentioning

confidence: 96%

“…Previously, we reported that HBXIP acted as an oncogenic coactivator for transcription factors in breast cancer (16,(22)(23)(24). Accordingly, we performed chromatin immunoprecipitation (ChIP) assays to determine whether HBXIP was involved in the transcriptional regulation of FAS.…”

Section: Hbxip Activates Fas Through Upregulation Of Srebp-1c Transcrmentioning

confidence: 99%

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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The oncoprotein HBXIP upregulates Lin28Bviaactivating TF II D to promote proliferation of breast cancer cells

Liu

Bai

et al. 2013

Int. J. Cancer

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Hepatitis B X-interacting protein (HBXIP) is a novel oncoprotein and plays a key role in the development of breast cancer. However, its mechanisms of action are poorly understood. Lin28B functions as an oncogene in a variety of human cancers. In our study, we report that HBXIP acts with its partner Lin28B to contribute to carcinogenesis. Our data showed that the expression levels of HBXIP were significantly positively correlated with those of Lin28B in clinical breast cancer tissues. Then, we found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells. Chromatin immunoprecipitation assay (ChIP) and electrophoretic mobility shift assay (EMSA) revealed that HBXIP occupied the promoter region (21199/-1073 nt) of Lin28B. Importantly, co-immunoprecipitation (Co-IP) and GST pull-down assay validated that HBXIP directly bound to the TATA-binding protein (TBP), a basal subunit of transcription factor TF II D complex. In addition, we discovered that Lin28B could block the downregulation of HBXIP via suppressing miR-520b which directly targeted HBXIP mRNA in the cells. In function, we demonstrated that HBXIP enhanced the proliferation of breast cancer cells through Lin28B in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner. Therapeutically, HBXIP may serve as a target of breast cancer.Hepatitis B X-interacting protein (HBXIP), a conserved 18KDa protein, is originally identified by its interaction with the hepatitis B virus X protein (HBx) and negatively regulates the activity of HBx and alters the replicative life cycle of the virus. 1 Expression of HBXIP mRNA occurs in nearly all tissues not limited to liver and is also in mice and other rodents. 2 The sequences of the HBXIP gene, containing a putative leucine zipper motif and two consensus phosphorylation sites for protein kinase C and casein kinase II, are well conserved among mammalian species. 1 HBXIP can regulate the duplication of centrosome and HBXIP-deficient Hela cells succumb eventually to apoptosis. In addition, a mouse model of liver regeneration experiment shows HBXIP is a critical regulator of hepatocyte cell growth in vivo. 3 Studies also report that HBXIP functions as a cofactor with survivin through forming a complex to suppress apoptosis. 2 Importantly, our group shows that HBXIP plays crucial roles in the development of breast cancer, serving as a key oncoprotein in cancer. [4][5][6][7] Recently, we show that HBXIP promotes the breast cancer cell growth by upregulating S100A4. 7 However, the mechanism by which HBXIP enhances the proliferation of breast cancer cells remains poorly understood.Lin28B, a homolog of Lin28, originally identified in hepatocellular carcinoma conserves a cold shock domain and a pair of CCHC zinc finger domains. 8 Lin28B i...

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The Oncoprotein HBXIP Uses Two Pathways to Up-regulate S100A4 in Promotion of Growth and Migration of Breast Cancer Cells

Cited by 72 publications

References 36 publications

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

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

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

The oncoprotein HBXIP upregulates Lin28Bviaactivating TF II D to promote proliferation of breast cancer cells

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