Hwa Young Yim

Sookmyung Women's University, Sŏul, Seoul, South Korea

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Publications (4)36.02 Total impact

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    ABSTRACT: The recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage- and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here we leverage these resources, to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes. Among a total of 1,455 category-specific expression patterns, the expression of cAMP phosphodiesterase-4D (PDE4D) with 11 isoforms, one of the PDE4(A-D) sub-families, was predicted to be regulated by a mutant form of Serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) present in lung cancer. STK11/LKB1 is the primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK). Subsequently, we found that the knockdown of PDE4D gene expression inhibited proliferation of STK11-mutated lung cancer lines. Furthermore, challenge with a panel of PDE4 specific inhibitors was shown to selectively reduce the growth of STK11-mutated lung cancer lines. Thus we show that multidimensional analysis of a well-characterized large-scale panel of cancer cell lines provides unprecedented opportunities for identification of unexpected oncogenic mechanisms and mutation-specific drug targets.
    Molecular Cancer Therapeutics 08/2014; 13(10). DOI:10.1158/1535-7163.MCT-14-0297 · 5.68 Impact Factor
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    ABSTRACT: UBP43 (also known as USP18) plays a role in the negative regulation of interferon-α/β signaling, and bone marrow cells in Ubp43-deficient mice exhibited hypersensitivity to interferon-α/β-mediated apoptosis. Here, we show that the mitochondrial apoptotic pathway and reactive oxygen species are major contributors to the elevated interferon-α/β-mediated apoptosis in Ubp43-deficient mouse bone marrow cells and in UBP43-knockdown THP-1 cells. Furthermore, TRAIL and FASL, which were proposed as apoptosis inducers upon interferon-α/β treatment in UBP43-knockdown adherent cancer cells, did not cause apoptosis in these hematopoietic cells. Therefore, although UBP43 depletion can cause hypersensitivity to interferon-α/β-mediated apoptosis in a broad range of cell types, the downstream pathway may vary depending on the cell type.
    Biochemical and Biophysical Research Communications 06/2012; 423(2):436-40. DOI:10.1016/j.bbrc.2012.05.154 · 2.30 Impact Factor
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    ABSTRACT: A critical component of the DNA damage response is the p53 tumor suppressor, and aberrant p53 function leads to uncontrolled cell proliferation and malignancy. Several molecules have been shown to regulate p53 stability; however, genome-wide systemic approaches for determining the affected, specific downstream target genes have not been extensively studied. Here, we first identified an orphan nuclear receptor, RORα, as a direct target gene of p53, which contains functional p53 response elements. The functional consequences of DNA damage-induced RORα are to stabilize p53 and activate p53 transcription in a HAUSP/Usp7-dependent manner. Interestingly, microarray analysis revealed that RORα-mediated p53 stabilization leads to the activation of a subset of p53 target genes that are specifically involved in apoptosis. We further confirmed that RORα enhances p53-dependent, in vivo apoptotic function in the Drosophila model system. Together, we determined that RORα is a p53 regulator that exerts its role in increased apoptosis via p53.
    Molecular cell 12/2011; 44(5):797-810. DOI:10.1016/j.molcel.2011.09.023 · 14.02 Impact Factor
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    ABSTRACT: Wnt family members play diverse roles in development and disease. Noncanonical Wnt ligands can inhibit canonical Wnt signaling depending on the cellular context; however, the underlying mechanism of this antagonism remains poorly understood. Here we identify a specific mechanism of orphan nuclear receptor RORalpha-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKCalpha-dependent phosphorylation on serine residue 35 of RORalpha is crucial to link RORalpha to Wnt/beta-catenin signaling, which exerts inhibitory function of the expression of Wnt/beta-catenin target genes. Intriguingly, there is a significant correlation of reduction of RORalpha phosphorylation in colorectal tumor cases compared to their normal counterpart, providing the clinical relevance of the findings. Our data provide evidence for a role of RORalpha, functioning at the crossroads between the canonical and the noncanonical Wnt signaling pathways, in mediating transrepression of the Wnt/beta-catenin target genes, thereby providing new approaches for the development of therapeutic agents for human cancers.
    Molecular cell 01/2010; 37(2):183-95. DOI:10.1016/j.molcel.2009.12.022 · 14.02 Impact Factor