Ke Yao

Henan Tianguan Group (China)

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Zigang Dong

China-US (Henan) Hormel Cancer Institute

Ann M. Bode

Royal Belfast Hospital for Sick Children

Yong‐Yeon Cho

Catholic University of Korea

Hanyong Chen

Hormel (United States)

Kangdong Liu

Zhengzhou University

Feng Zhu

Wenzhou City People's Hospital

Tatyana A. Zykova

Ministry of Health of the Russian Federation

Cong Peng

Xiangya Hospital Central South University

Weiya Ma

McGill University

Ziming Dong

Zhengzhou University

Cooperative Institutions

University of Minnesota

103

Hormel (United States)

Zhengzhou University

China-US (Henan) Hormel Cancer Institute

Seoul National University

Chinese Academy of Sciences

Henan Cancer Hospital

First Affiliated Hospital of Zhengzhou University

Kyungpook National University

Central South University

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Targeting nutrient metabolism with FDA-approved drugs for cancer chemoprevention: Drugs and mechanisms

Cancer Letters (2021)

Yifei Xie Ke Yao Zigang Dong Kangdong Liu

10.1016/j.canlet.2021.03.029

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Citations (9)

RSK2 is required for TRAF6 phosphorylation-mediated colon inflammation

Oncogene (2018)

Ke Yao Sungyoung Lee Cong Peng Do Young Lim Hiroyuki Yamamoto

Proinflammatory cytokine

IκB kinase

10.1038/s41388-018-0167-6

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Citations (15)

ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal

Stem Cell Research (2014)

Sung-Hyun Kim Myoung Ok Kim Yong‐Yeon Cho Ke Yao Dong Joon Kim

Nanog regulates human and mouse embryonic stem (ES) cell self-renewal activity. Activation of ERKs signaling negatively regulates ES cell self-renewal and induces differentiation, but the mechanisms are not understood. We found that ERK1 binds and phosphorylates Nanog. Activation of MEK/ERKs signaling and phosphorylation of Nanog inhibit Nanog transactivation, inducing ES cell differentiation. Conversely, suppression of MEK/ERKs signaling enhances Nanog transactivation to inhibit ES cell differentiation. We observed that phosphorylation of Nanog by ERK1 decreases Nanog stability through ubiquitination-mediated protein degradation. Further, we found that this phosphorylation induces binding of FBXW8 with Nanog to reduce Nanog protein stability. Overall, our results demonstrated that ERKs-mediated Nanog phosphorylation plays an important role in self-renewal of ES cells through FBXW8-mediated Nanog protein stability.

Homeobox protein NANOG

Nanog Homeobox Protein

Rex1

10.1016/j.scr.2014.04.001

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Citations (105)

HOI-02 induces apoptosis and G2-M arrest in esophageal cancer mediated by ROS

Cell Death and Disease (2015)

Chen Zhang K Liu Ke Yao K. Thammi Reddy Yi Zhang

Abstract Reactive oxygen species (ROS) are chemically reactive molecules that perform essential functions in living organisms. Accumulating evidence suggests that many types of cancer cells exhibit elevated levels of ROS. Conversely, generation of ROS has become an effective method to kill cancer cells. (E)-3-hydroxy-3-(4-(4-nitrophenyl)-2-oxobut-3-en-1-yl) indolin-2-one, which is an NO 2 group-containing compound designated herein as HOI-02, generated ROS and, in a dose-dependent manner, decreased esophageal cancer cell viability and inhibited anchorage-independent growth, followed by apoptosis and G2-M arrest. Moreover, results of an in vivo study using a patient-derived xenograft mouse model showed that HOI-02 treatment suppressed the growth of esophageal tumors, without affecting the body weight of mice. The expression of Ki-67 was significantly decreased with HOI-02 treatment. In addition, the phosphorylation of c-Jun, and expression of p21, cleaved caspase 3, and DCFH-DA were increased in the HOI-02-treated group compared with the untreated control group. In contrast, treatment of cells with (E)-3-(4-(4-aminophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one, which is an NH 2 group-containing compound designated herein as HOI-11, had no effect. Overall, we identified HOI-02 as an effective NO 2 group-containing compound that was an effective therapeutic or preventive agent against esophageal cancer cell growth.

Viability assay

10.1038/cddis.2015.227

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Citations (18)

Eriodictyol Inhibits RSK2-ATF1 Signaling and Suppresses EGF-induced Neoplastic Cell Transformation

Journal of Biological Chemistry (2010)

Kangdong Liu Yong‐Yeon Cho Ke Yao Janos Nadas Dong Joon Kim

RSK2 is a widely expressed serine/threonine kinase, and its activation enhances cell proliferation. Here, we report that ATF1 is a novel substrate of RSK2 and that RSK2-ATF1 signaling plays an important role in EGF-induced neoplastic cell transformation. RSK2 phosphorylated ATF1 at Ser-63 and enhanced ATF1 transcriptional activity. Docking experiments using the crystal structure of the RSK2 N-terminal kinase domain combined with in vitro pulldown assays demonstrated that eriodictyol, a flavanone found in fruits, bound with the N-terminal kinase domain of RSK2 to inhibit RSK2 N-terminal kinase activity. In cells, eriodictyol inhibited phosphorylation of ATF1 but had no effect on the phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically suppresses RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation and tumor promoter-induced transformation of JB6 Cl41 cells. Eriodictyol or knockdown of RSK2 or ATF1 also suppressed Ras-mediated focus formation. Overall, these results indicate that RSK2-ATF1 signaling plays an important role in neoplastic cell transformation and that eriodictyol is a novel natural compound for suppressing RSK2 kinase activity.

Eriodictyol

Neoplastic transformation

10.1074/jbc.m110.147306

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Citations (62)

Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032

Oncogene (2020)

Eunmiri Roh Yaping Han Kanamata Reddy Tatyana A. Zykova Mee Hyun Lee

Hairless

10.1038/s41388-020-1286-4

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Citations (15)

Phosphorylation of H2AX at Ser139 and a New Phosphorylation Site Ser16 by RSK2 Decreases H2AX Ubiquitination and Inhibits Cell Transformation

Cancer Research (2011)

Feng Zhu Tatyana A. Zykova Cong Peng Jishuai Zhang Yong‐Yeon Cho

Histone H2AX is a histone H2A variant that is ubiquitously expressed throughout the genome. It plays a key role in the cellular response to DNA damage and has been designated as the histone guardian of the genome. Histone H2AX deficiency decreases genomic stability and increases tumor susceptibility of normal cells and tissues. However, the role of histone H2AX phosphorylation in malignant transformation and cancer development is not totally clear. Herein, we found that ribosomal S6 kinase 2 (RSK2) directly phosphorylates histone H2AX at Ser139 and also at a newly discovered site, Ser16. Epidermal growth factor (EGF)-induced phosphorylation of histone H2AX at both sites was decreased in RSK2 knockout cells. Phosphorylated RSK2 and histone H2AX colocalized in the nucleus following EGF treatment, and the phosphorylation of histone H2AX by RSK2 enhanced the stability of histone H2AX and prevented cell transformation induced by EGF. RSK2 and DNA-PK, but not ATM or ATR, are required for EGF-induced phosphorylation of H2AX at Ser139; however, only RSK2 is required for phosphorylation of H2AX at Ser16. Phosphorylation of histone H3 was suppressed in cells expressing wild-type H2AX compared with H2AX knockout (H2AX-/-) cells. EGF-associated AP-1 transactivation activity was dramatically lower in H2AX-/- cells overexpressing wild-type H2AX than H2AX-/- cells expressing mutant H2AX-AA. Thus, the RSK2/H2AX signaling pathway negatively regulates the RSK2/histone H3 pathway and therefore maintains normal cell proliferation.

10.1158/0008-5472.can-10-2012

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Citations (35)

GSK3β-Mediated Expression of CUG-Translated WT1 Is Critical for Tumor Progression

Cancer Research (2020)

Hisae Yoshitomi Kun Y. Lee Ke Yao Seung Ho Shin Tianshun Zhang

Abstract The Wilms' tumor 1 (WT1) gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box−/− WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. Significance: These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.

Tumor progression

Expression (computer science)

10.1158/0008-5472.can-20-1880

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Citations (5)

Targeting ornithine decarboxylase (ODC) inhibits esophageal squamous cell carcinoma progression

npj Precision Oncology (2017)

Wei He Eunmiri Roh Ke Yao Kangdong Liu Xing Meng

Abstract To explore the function of ornithine decarboxylase in esophageal squamous cell carcinoma progression and test the effectiveness of anti-ornithine decarboxylase therapy for esophageal squamous cell carcinoma. In this study, we examined the expression pattern of ornithine decarboxylase in esophageal squamous cell carcinoma cell lines and tissues using immunohistochemistry and Western blot analysis. Then we investigated the function of ornithine decarboxylase in ESCC cells by using shRNA and an irreversible inhibitor of ornithine decarboxylase, difluoromethylornithine. To gather more supporting pre-clinical data, a human esophageal squamous cell carcinoma patient-derived xenograft mouse model (C.B-17 severe combined immunodeficient mice) was used to determine the antitumor effects of difluoromethylornithine in vivo. Our data showed that the expression of the ornithine decarboxylase protein is increased in esophageal squamous cell carcinoma tissues compared with esophagitis or normal adjacent tissues. Polyamine depletion by ODC shRNA not only arrests esophageal squamous cell carcinoma cells in the G2/M phase, but also induces apoptosis, which further suppresses esophageal squamous cell carcinoma cell tumorigenesis. Difluoromethylornithine treatment decreases proliferation and also induces apoptosis of esophageal squamous cell carcinoma cells and implanted tumors, resulting in significant reduction in the size and weight of tumors. The results of this study indicate that ornithine decarboxylase is a promising target for esophageal squamous cell carcinoma therapy and difluoromethylornithine warrants further study in clinical trials to test its effectiveness against esophageal squamous cell carcinoma.

Squamous carcinoma

10.1038/s41698-017-0014-1

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Citations (21)

Abstract 1080: Computational and biochemical discovery of RSK2 as a novel target for epigallocatechin gallate (EGCG)

Cancer Research (2015)

Hanyong Chen Ke Yao Xiaoyu Chang Jung‐Hyun Shim Hong-Gyum Kim

Abstract The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). Protein interaction with EGCG is a critical step mediating the effects of EGCG on the regulation of various key proteins involved in signal transduction. By using computational docking screening methods for protein identification, we identified a serine/threonine kinase, 90-kDa ribosomal S6 kinase (RSK2), as a novel molecular target of EGCG. RSK2 includes two kinase catalytic domains in the N-terminal (NTD) and the C-terminal (CTD) and its activation requires phosphorylation of both the NTD and CTD. The computer prediction was confirmed by an in vitro kinase assay in which EGCG inhibited RSK2 activity in a dose-dependent manner. Pull-down assay results showed that EGCG could bind with RSK2 at both kinase catalytic domains in vitro and ex vivo. Furthermore, results of an ATP competition assay and a computer-docking model showed that EGCG binds with RSK2 in an ATP-dependent manner. In RSK2+/+ and RSK2-/- murine embryonic fibroblasts, EGCG decreased viability only in the presence of RSK2. EGCG also suppressed epidermal growth factor-induced neoplastic cell transformation by inhibiting histone H3 Ser10 phosphorylation. Overall, these results indicate that EGCG is a novel natural compound for suppressing RSK2 kinase activity. Citation Format: Hanyong Chen, Ke Yao, Xiaoyu Chang, Jung-Hyun Shim, Hong-Gyum Kim, Margarita Malakhova, Dong-Joon Kim, Ann M. Bode, Zigang Dong. Computational and biochemical discovery of RSK2 as a novel target for epigallocatechin gallate (EGCG). [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 1080. doi:10.1158/1538-7445.AM2015-1080

Docking (animal)

Ribosomal s6 kinase

10.1158/1538-7445.am2015-1080

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Citations (0)