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  • American Association for Cancer Research (AACR)  (6)
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  • American Association for Cancer Research (AACR)  (6)
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  • 1
    Online Resource
    Online Resource
    Abstract 5154: Targeting the histone demethylase KDM4 subfamily as a potential therapeutic strategy in breast cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5154-5154
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5154-5154
    Abstract: Epigenetic alterations, including histone modifications, play fundamental roles in breast cancer initiation and progression. We originally identified and cloned the GASC1 (gene amplified in squamous cell carcinoma 1, also known as KDM4C) gene from an amplified region at 9p24 in esophageal cancer cells; and recently demonstrated that KDM4C/GASC1 is amplified and over-expressed in breast cancer, particularly in the aggressive basal subtype. The KDM4C/GASC1 protein belongs to the KDM4 family of histone demethylases, and although KDM4 family members have a high degree of homology, they may play different roles in various types of breast cancer. The goal of this study is to analyze genomic anomalies and expression levels of KDM4 demethylases in breast cancer, and elucidate the fundamental role and mechanism of their dysregulation in promoting breast tumorigenesis. We conducted a large-scale meta-analysis of KDM4 demethylase expression across multiple available gene expression studies in breast cancer. Next, we examined KDM4 expression in a panel of non-tumorigenic and cancerous breast epithelial cell lines using quantitative RT-PCR and Western blot assays. We also assessed global methylation (H3K4, H3K9, H3K27 and H3K36) levels by Western blot in a panel of breast cancer cell lines. Finally, we tested a novel KDM4 inhibitor in breast cancer. We found that the KDM4 members show different expression patterns in subtypes of breast cancer. GASC1/KDM4C expression is high in estrogen receptor (ER)-negative, basal type breast cancers. In contrast, KDM4B expression is significantly higher in ER-positive luminal-type breast cancers. Expression levels of homologs KDM4A and D are not significantly different between ER-+/- breast cancers. Our findings suggest that H3 global methylation levels vary among different breast cancer cell lines. Furthermore, we demonstrated that inhibition of KDM4 with a novel small molecule inhibitor increased H3K9 methylation levels and slowed KDM4-overexpressed breast cancer cell growth in vitro. In summary, our data indicate that the KDM4 histone demethylase family may contribute to the dysregulation of histone methylation status differently in breast cancer subtypes. Moreover, breast cancer cell lines with defined histone methylation levels will provide a useful model for investigating biological and functional roles of KDM4 histone demethylases, and for developing novel anticancer epi-drugs in breast cancer. Citation Format: Andreana Holowatyj, Qin Ye, Lihong Zhang, Jack Wu, Zeng-Quan Yang. Targeting the histone demethylase KDM4 subfamily as a potential therapeutic strategy in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5154. doi:10.1158/1538-7445.AM2014-5154
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-5154
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Abstract 98: Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 98-98
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 98-98
    Abstract: The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. Although KDM4 family members have a high degree of homology, they may play different roles in various types of breast cancer. The goal of this study is to analyze the genomic and transcriptomic alterations of the KDM4 subfamily in different subtypes of breast cancer, and explore the therapeutic potential of a novel KDM4 inhibitor in aggressive basal breast cancer. We conducted a large-scale meta-analysis of KDM4A, B, C, and D in breast cancer and identified associations among recurrent copy number alterations, gene expression and breast cancer subtypes. We examined KDM4 expression in a panel of non-tumorigenic and cancerous breast epithelial cell lines using quantitative RT-PCR and Western blot assays, and assessed global histone 3 methylation levels by Western blot in a panel of breast cancer cell lines. Next, we tested a novel inhibitor of the KDM4 demethylases, small molecule NCDM-32B, for its ability to attenuate basal breast cancer cell growth and impair metastatic potential. Finally, to examine gene expression changes induced by NCDM-32B, we conducted expression profiling and pathway analyses. We found that the KDM4 members show different expression patterns in subtypes of breast cancer. Our findings suggest that H3 global methylation levels vary among different breast cancer cell lines. We demonstrated that NCDM-32B significantly impaired viability, cellular growth and transforming phenotypes of basal breast cancer in vitro. Furthermore, NCDM-32B impaired several critical pathways and classical oncogenes, including MET, CDC26, and CDK6, that drive cellular proliferation and transformation in breast cancer. In summary, our findings add layers of information to the genomic and transcriptomic profiles of the KDM4 subfamily in different subtypes of breast cancer. We provide the first evidence that a novel KDM4 demethylase inhibitor, the small molecule NCDM-32B, led to significant inhibition of cellular growth of basal breast cancer in vitro. These findings lay the foundation for evaluating KDM4 inhibitors as therapeutic approaches against aggressive breast cancer. Citation Format: Andreana N. Holowatyj, Qin Ye, Jack Wu, Hui Liu, Lihong Zhang, Takayoshi Suzuki, Zeng-Quan Yang. Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 98. doi:10.1158/1538-7445.AM2015-98
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-98
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 2 ( 2016-01-15), p. 293-304
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 2 ( 2016-01-15), p. 293-304
    Abstract: 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-Myc–mediated 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 long-standing questions on how c-Myc drives carcinogenesis. Cancer Res; 76(2); 293–304. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-3607
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Long Noncoding RNA HULC Modulates Abnormal Lipid Metabolism in Hepatoma Cells through an miR-9–Mediated RXRA Signaling Pathway
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 5 ( 2015-03-01), p. 846-857
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 5 ( 2015-03-01), p. 846-857
    Abstract: HULC is a long noncoding RNA overexpressed in hepatocellular carcinoma (HCC), but its functional contributions in this setting have not been determined. In this study, we explored the hypothesis that HULC contributes to malignant development by supporting abnormal lipid metabolism in hepatoma cells. HULC modulated the deregulation of lipid metabolism in HCC by activating the acyl-CoA synthetase subunit ACSL1. Immunohistochemical analysis of tissue microarrays revealed that approximately 77% (180/233) of HCC tissues were positive for ACSL1. Moreover, HULC mRNA levels correlated positively with ACSL1 levels in 60 HCC cases according to real-time PCR analysis. Mechanistic investigations showed that HULC upregulated the transcriptional factor PPARA, which activated the ACSL1 promoter in hepatoma cells. HULC also suppressed miR-9 targeting of PPARA mRNA by eliciting methylation of CpG islands in the miR-9 promoter. We documented the ability of HULC to promote lipogenesis, thereby stimulating accumulation of intracellular triglycerides and cholesterol in vitro and in vivo. Strikingly, ACSL1 overexpression that generates cholesterol was sufficient to enhance the proliferation of hepatoma cells. Further, cholesterol addition was sufficient to upregulate HULC expression through a positive feedback loop involving the retinoid receptor RXRA, which activated the HULC promoter. Overall, we concluded that HULC functions as an oncogene in hepatoma cells, acting mechanistically by deregulating lipid metabolism through a signaling pathway involving miR-9, PPARA, and ACSL1 that is reinforced by a feed-forward pathway involving cholesterol and RXRA to drive HULC signaling. Cancer Res; 75(5); 846–57. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-1192
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Abstract 5152: Mechanism and therapeutic potential of the histone demethylase GASC1 in castration-resistant prostate cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5152-5152
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5152-5152
    Abstract: The histone lysine demethylase, GASC1 (Gene Amplified in Squamous Cell Carcinoma 1) is an epigenetic regulatory protein both highly expressed during mammalian embryogenesis and overexpressed in several types of cancer, including aggressive Castration Resistant Prostate Cancer (CRPC). GASC1 mainly catalyzes demethylation of tri- and di-methylated forms of histone H3 lysine 9 (H3K9me3/me2) epigenetic repressive marks, regulating gene expression and chromatin architecture. This research aims to elucidate the fundamental mechanism by which GASC1 dysregulation contributes to CRPC progression, as well as to evaluate its potential as a therapeutic target against aggressive prostate cancer. Previously, our lab and others have shown that GASC1 interacts with the androgen receptor (AR) and functions as a co-activator of AR-induced transcription in prostate cancer. We have used an shRNA approach to determine whether GASC1 knockdown affects the proliferation and transformation of CRPC cells. We found that knocking down GASC1 inhibits the growth and colony formation of C4-2B and CWR22Rv1 cells in vitro. Knockdown also reduced transcript levels of classical and CRPC-specific AR target genes in either the presence or absence of the AR ligand. As a result, we are evaluating the therapeutic potential of novel and highly specific lysine demethylase inhibitors towards abating GASC1 function in prostate cancer cells in vitro. We have recently determined that one of these novel inhibitors is highly effective in modulating the survival and proliferation of several prostate cancer cell lines including CRPC lines with IC50 values, all well under 1 uM. Together, our data demonstrates that GASC1 is a therapeutically relevant target in controlling and preventing the emergence of prostate cancers, with particular application against aggressive CRPC subtypes. Citation Format: Roselyne M. Labbe, Qin Ye, Andreana Holowatyj, Lihong Zhang, Zeng Quan Yang. Mechanism and therapeutic potential of the histone demethylase GASC1 in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5152. doi:10.1158/1538-7445.AM2014-5152
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-5152
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 16 ( 2016-08-15), p. 4696-4707
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 16 ( 2016-08-15), p. 4696-4707
    Abstract: 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 X-interacting 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 ligand-dependent 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. Cancer Res; 76(16); 4696–707. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-1734
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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