Kibeom Jang

Sylvester Comprehensive Cancer Center

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Minsoon Kim

Sylvester Comprehensive Cancer Center

Joyce M. Slingerland

University of Miami

Dekuang Zhao

Shanghai Tenth People's Hospital

Tan A. Ince

NewYork–Presbyterian Brooklyn Methodist Hospital

Diana J. Azzam

Florida International University

Seth A. Wander

Harvard University

Alexandra H. Besser

University of California, San Diego

Hyunho Yoon

Sylvester Comprehensive Cancer Center

Burcu Ergonul

Sylvester Comprehensive Cancer Center

Pablo Torné‐Poyatos

Instituto de Investigación Biosanitaria de Granada

Cooperative Institutions

University of Miami

Sylvester Comprehensive Cancer Center

Georgetown University

University of California, San Francisco

Hanyang University

Georgetown University Medical Center

Universidad de Granada

The University of Texas MD Anderson Cancer Center

Konkuk University

Korea Research Institute of Bioscience and Biotechnology

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C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer

Nature Communications (2024)

Seyedeh Fatemeh Razavipour Hyunho Yoon Kibeom Jang Minsoon Kim Hend M. Nawara

Abstract In many cancers, a stem-like cell subpopulation mediates tumor initiation, dissemination and drug resistance. Here, we report that cancer stem cell (CSC) abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistically, this arises through p27 co-recruitment with STAT3/CBP to gene regulators of CSC self-renewal including MYC , the Notch ligand JAG1 , and ANGPTL4 . p27pTpT/STAT3 also recruits a SIN3A/HDAC1 complex to co-repress the Pyk2 inhibitor, PTPN12 . Pyk2, in turn, activates STAT3, creating a feed-forward loop increasing stem-like properties in vitro and tumor-initiating stem cells in vivo. The p27-activated gene profile is over-represented in STAT3 activated human breast cancers. Furthermore, mammary transgenic expression of phosphomimetic, cyclin-CDK-binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis, yielding hyperplasia and microinvasive cancers that can metastasize to liver, further supporting a role for p27pTpT in CSC expansion. Thus, p27pTpT interacts with STAT3, driving transcriptional programs governing stem cell expansion or maintenance in normal and cancer tissues.

10.1038/s41467-024-48742-y

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음악교육의 융합교육 접근을 위한 융합 개념 논의

Kim Kyoung Hwa Kibeom Jang

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포괄적 음악영재 교육을 위한 음악영재의 판별방법과 교육 프로그램에 관한 연구

Kibeom Jang Moon-Jung Yoon

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Abstract 504: p27 transcriptionally coregulates STAT3 to drive cancer stem cells

Cancer Research (2020)

Seyedehfatemeh Razavipour Kibeom Jang Hyunho Yoon Minsoon Kim Miyoung Shin

Abstract p27 is a cell cycle inhibitor and a tumor suppressor. It can also regulate cellular processes including migration and transcription through mechanisms independent of its CDK-inhibitory role. In cancers, p27 C-terminal phosphorylation by PI3K-activated kinases, AKT, RSK1, and SGK1 at T157 and T198 alters p27 protein-protein interactions and shifts p27 from CDK-inhibitor to an oncogene. Previously, our group showed that CDK-binding defective p27pT157pT198 phosphomimetic (p27CK-DD) upregulates epithelial-mesenchymal transition (EMT) and the metastatic potential of cancer cell lines. In addition to its action to promote EMT, p27 appears to promote CSC expansion and or maintenance. Here we demonstrated that C-terminally phosphorylated p27 increases CSC properties, including tumor sphere formation and CSC markers. p27CK-DD increases the expression of several embryonic stem cell transcription factors (ES-TFs), including SOX2, NANOG and cMYC, which are known to drive embryonic stem cell self-renewal and to promote CSC expansion. A human phospho-kinase array showed Pyk2 is activated by p27CK-DD. We demonstrated that Pyk2 activation and its binding to p27 are dependent on phosphorylation of p27 at T198 and T157. Treatment with a Pyk2 inhibitor, and PYK2-knockdown by siRNA or shRNA revealed that Pyk2 is a key mediator of the increase in tumor spheres, ALDH1 activity and ES-TFs in cancer cells expressing abundant C-terminally phosphorylated p27. Pyk2 enhances STAT3 phosphorylation and activation. We identified that C-terminally phosphorylated p27 recruits STAT3 to form p27-Pyk2-STAT3 complex leading to STAT3 activation. p27/STAT3 complexes co-localize to the nucleus and co-occupy chromatin. We confirmed by ChIP-qPCR that p27/STAT3 bind and activate the cMYC promotor. Altogether, in breast cancer cells with high p27pT157pT198 or expressing p27CK−DD, STAT3 is partly activated by Pyk2 and interacts with p27. p27 is a STAT3 coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. These data reveal a novel mechanism whereby p27-driven Pyk2 activation promotes CSC expansion and tumor progression via transcriptionally activation of the STAT3 and its target genes. Citation Format: Seyedehfatemeh Razavipour, Kibeom Jang, Hyunho Yoon, Minsoon Kim, Miyoung Shin, Dekuang Zhao, Joyce Slingerland. p27 transcriptionally coregulates STAT3 to drive cancer stem cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 504.

Homeobox protein NANOG

CDK inhibitor

10.1158/1538-7445.am2020-504

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Data from Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression

Manuel Picon‐Ruiz Chendong Pan Katherine Drews‐Elger Kibeom Jang Alexandra H. Besser

<div>AbstractConsequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell–like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. Cancer Res; 76(2); 491–504. ©2016 AACR.</div>

10.1158/0008-5472.c.6507570

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CD24 enhances DNA damage-induced apoptosis by modulating NF-κB signaling in CD44-expressing breast cancer cells

Carcinogenesis (2011)

Ji-hyun Ju Kibeom Jang Kyung‐min Lee Minsoon Kim Jongbin Kim

Cluster of differentiation 24 (CD24) is a small glycosylphosphatidylinositol-linked cell surface molecule that is expressed in a variety of human carcinomas, including breast cancer. To determine the role of CD24 in breast cancer cells, we expressed CD24 in CD24-negative/low and cluster of differentiation 44 (CD44)-positive MDA-MB-231 metastatic breast cancer cells. Forced expression of CD24 resulted in a decrease in c-Raf/mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/mitogen-activated protein kinase signaling and reduced cell proliferation. Apoptosis induced by DNA damage was greatly enhanced in MDA-MB-231 CD24 cells as compared with MDA-MB-231 vec cells. CD24 expression efficiently attenuated DNA damage-induced nuclear factor-kappaB (NF-κB) signaling in MDA-MB-231 cells. However, in CD24-positive and CD44-negative/low MCF-7 cells, knockdown of CD24 did not significantly affect DNA damage-induced apoptosis nor NF-κB signaling. Silencing of CD24 in CD24/CD44-double-positive MDA-MB-468 cells partially rescued DNA damage-induced apoptosis. Transient transfection studies with 293T cells also revealed that CD24 attenuated cell viability and NF-κB signaling only when CD44 was cotransfected. These data indicate that CD24 expression potentiated DNA-induced apoptosis by suppressing antiapoptotic NF-κB signaling in CD44-expressing cells.

CD24

10.1093/carcin/bgr173

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Data from Dual Src and MEK Inhibition Decreases Ovarian Cancer Growth and Targets Tumor Initiating Stem-Like Cells

Fiona Simpkins Kibeom Jang Hyunho Yoon Karina E. Hew Minsoon Kim

<div>AbstractPurpose: Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition.Experimental Design: MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene, and proteomic analysis; cancer stem cells; and xenografts.Results: Both Src and MAPK are coactivated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell-cycle arrest in vitro, and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout decreased sphere formation and ALDH1+ cells. In vivo, tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation, and loss of tumor-initiating cells upon serial xenografting.Conclusions: Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2–mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating ovarian cancer populations, supporting further evaluation of combined Src–MEK inhibition in clinical trials. Clin Cancer Res; 24(19); 4874–86. ©2018 AACR.</div>

Selumetinib

10.1158/1078-0432.c.6527202

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Supplementary Figures S1-S6 from Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression

Manuel Picon‐Ruiz Chendong Pan Katherine Drews‐Elger Kibeom Jang Alexandra H. Besser

hASC characterization (S1); Co-culture of immature adipocytes with mammary epithelial cells increases pro-inflammatory cytokine expression (S2); Immature adipocyte or cytokine exposure increases abundance of sphere and colony forming cells without changing global cell proliferation (S3); Immature adipocyte or cytokine exposure increases matrigel invasion in vitro and tumor formation, vasculogenesis and metastasis in vivo (S4); Src mediates cytokine effects via ES-TF upregulation affecting soft agar colony growth but not cell cycle progression (S5); Cytokine-mediated increase in sphere formation is Sox2-dependent and miR302b upregulation drives further c-MYC and SOX2 gene expression (S6).

Matrigel

10.1158/0008-5472.22408620.v1

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Induction of apoptotic cell death by phytoestrogens by up-regulating the levels of phospho-p53 and p21 in normal and malignant estrogen receptor α–negative breast cells

Nutrition Research (2011)

Hye‐Sook Seo Ji‐hyun Ju Kibeom Jang Incheol Shin

Apoptotic cell death

10.1016/j.nutres.2011.01.011

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Supplementary Figure Legends from Dual Src and MEK Inhibition Decreases Ovarian Cancer Growth and Targets Tumor Initiating Stem-Like Cells

Fiona Simpkins Kibeom Jang Hyunho Yoon Karina E. Hew Minsoon Kim

Supplementary Figure Legends

10.1158/1078-0432.22469298

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