Huafei Zou

Sun Yat-sen University

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Weijun Shen

Scripps Research Institute

Peter G. Schultz

Scripps Research Institute

Danling Wang

University of South China

Elizabeth Chao

Ambry Genetics (United States)

Pengyu Yang

Northeastern University

Jennifer R. Grandis

University of California, San Francisco

Zhenwen Yan

UPMC Hillman Cancer Center

A. James Mixson

University of Maryland, Baltimore

Vân Nguyên-Trân

Scripps Research Institute

Luyuan Li

Nankai University

Cooperative Institutions

California Institute for Biomedical Research

Scripps Research Institute

University of Pittsburgh

Scripps (United States)

Scripps Institution of Oceanography

UPMC Hillman Cancer Center

Fudan University

Peking University

Genomics Institute of the Novartis Research Foundation

Chinese Academy of Sciences

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Oxidative Stress-induced Inhibition of Sirt1 by Caveolin-1 Promotes p53-dependent Premature Senescence and Stimulates the Secretion of Interleukin 6 (IL-6)

Journal of Biological Chemistry (2014)

Daniela Volonté Huafei Zou Janine N. Bartholomew Zhongmin Liu Penelope A. Morel

Caveolin 1

Sirtuin 1

Senescence

10.1074/jbc.m114.598268

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Citations (94)

A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening

Scientific Reports (2017)

Sang Jun Lee Madhupriya Mahankali Abdallah Bitar Huafei Zou Elizabeth Chao

Elevated triglyceride (TG) levels are well-correlated with the risk for cardiovascular disease (CVD). Apolipoprotein CIII (ApoC-III) is a key regulator of plasma TG levels through regulation of lipolysis and lipid synthesis. To identify novel regulators of TG levels, we carried out a high throughput screen (HTS) using an ApoC-III homogenous time resolved fluorescence (HTRF) assay. We identified several retinoic acid receptor (RAR) agonists that reduced secreted ApoC-III levels in human hepatic cell lines. The RARα specific agonist AM580 inhibited secreted ApoC-III by >80% in Hep3B cells with an EC50 ~2.9 nM. In high-fat diet induced fatty-liver mice, AM580 reduced ApoC-III levels in liver as well as in plasma (~60%). In addition, AM580 treatment effectively reduced body weight, hepatic and plasma TG, and total cholesterol (TC) levels. Mechanistically, AM580 suppresses ApoC-III synthesis by downregulation of HNF4α and upregulation of SHP1 expression. Collectively, these studies suggest that an RARα specific agonist may afford a new strategy for lipid-lowering and CVD risk reduction.

10.1038/s41598-017-05163-w

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New Generation Oxyntomodulin Peptides with Improved Pharmacokinetic Profiles Exhibit Weight Reducing and Anti-Steatotic Properties in Mice

Bioconjugate Chemistry (2020)

Pengyu Yang Huafei Zou Zaid Amso Candy Lee David Huang

Oxyntomodulin (OXM) is an intestinal peptide hormone that activates both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The natural peptide reduces body weight in obese subjects and exhibits direct acute glucoregulatory effects in patients with type II diabetes. However, the clinical utility of OXM is limited due to its lower in vitro potency and short in vivo half-life. To overcome these issues, we developed stapled, long-acting, and highly potent OXM analogs with balanced activities at both GLP-1 and GCG receptors. The lead molecule O14 exhibits potent and long-lasting effects on glucose control, body weight loss, and reduction of hepatic fat reduction in DIO mice. Importantly, O14 significantly reversed hepatic steatosis; reduced liver weight, total cholesterol, and hepatic triglycerides; and improved markers of liver function in a nonalcoholic steatohepatitis (NASH) mouse model. A symmetrical version of the peptide was also shown to be more efficacious and long-lasting in controlling glucose than semaglutide and the clinical candidate cotadutide in wild-type mice, highlighting the utility of our designs of the dual agonist as a potential new therapy for diabetes and liver diseases.

Steatosis

10.1021/acs.bioconjchem.0c00093

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Citations (26)

Apoptotic activity of genistein on human lung adenocarcinoma SPC-A-1 cells and preliminary exploration of its mechanisms using microarray

Biomedicine & Pharmacotherapy (2008)

Huafei Zou Shu-Xuan Zhan Kai-Ming Cao

10.1016/j.biopha.2007.12.010

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Human rhomboid family‐1 geneRHBDF1participates in GPCR‐mediated transactivation of EGFR growth signals in head and neck squamous cancer cells

The FASEB Journal (2008)

Huafei Zou Sufi M. Thomas Zhenwen Yan Jennifer R. Grandis Andreas Vogt

Epidermal growth factor receptor (EGFR) is an activated oncogene in many cancers. It can be transactivated by ligands of G protein-coupled receptors (GPCRs). We show here that a novel gene, human rhomboid family-1 (RHBDF1), which was recently reported to have a pivotal role in epithelial cancer cell growth in culture and in xenograft tumors, participates in the modulation of GPCR-mediated EGFR transactivation. The RHBDF1 protein localizes mainly in the endoplasmic reticulum. Silencing the RHBDF1 gene in head and neck squamous cancer cell line 1483 cells with siRNA causes an inhibition of gastrin-releasing peptide (GRP) -induced phosphorylation of EGFR and EGFR-dependent signaling proteins p44/42 MAPK and AKT, accompanied by an inhibition of GRP-induced survival, proliferation, and invasion of the cells. The EGFR signaling pathway itself remains intact, however, as the cells remain responsive to exogenous EGF. In addition, RHBDF1 gene silencing disrupts GRP-stimulated secretion of EGFR ligand TGF-alpha, but not the production of latent TGF-alpha, whereas engineered overexpression of RHBDF1 markedly accelerates the secretion of TGF-alpha. These findings are consistent with the view that RHBDF1 is critically involved in a GPCR ligand-stimulated process leading to the activation of latent EGFR ligands.

10.1096/fj.08-112771

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Citations (77)

Multifunctional Antibody Agonists Targeting Glucagon‐like Peptide‐1, Glucagon, and Glucose‐Dependent Insulinotropic Polypeptide Receptors

Angewandte Chemie (2016)

Ying Wang Jintang Du Huafei Zou Yan Liu Yuhan Zhang

Abstract Glucagon‐like peptide‐1 (GLP‐1) receptor (GLP‐1R), glucagon (GCG) receptor (GCGR), and glucose‐dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) receptor (GIPR), are three metabolically related peptide hormone receptors. A novel approach to the generation of multifunctional antibody agonists that activate these receptors has been developed. Native or engineered peptide agonists for GLP‐1R, GCGR, and GIPR were fused to the N‐terminus of the heavy chain or light chain of an antibody, either alone or in pairwise combinations. The fusion proteins have similar in vitro biological activities on the cognate receptors as the corresponding peptides, but circa 100‐fold longer plasma half‐lives. The GLP‐1R mono agonist and GLP‐1R/GCGR dual agonist antibodies both exhibit potent effects on glucose control and body weight reduction in mice, with the dual agonist antibody showing enhanced activity in the latter.

Gastric inhibitory polypeptide

Glucagon receptor

10.1002/ange.201606321

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Data from Human rhomboid family-1 gene silencing causes apoptosis or autophagy to epithelial cancer cells and inhibits xenograft tumor growth

Zhenwen Yan Huafei Zou Fang Tian Jennifer R. Grandis A. James Mixson

<div>Abstract<p>The rhomboid family of genes carry out a wide range of important functions in a variety of organisms. Little is known, however, about the function of the human rhomboid family-1 gene (RHBDF1). We show here that RHBDF1 function is essential to epithelial cancer cell growth. RHBDF1 mRNA level is significantly elevated in clinical specimens of invasive ductal carcinoma of the breast, and the protein is readily detectable in human breast cancer or head and neck cancer cell lines. Silencing the RHBDF1 gene with short interfering RNA (siRNA) results in apoptosis in breast cancer MDA-MB-435 cells and autophagy in head and neck squamous cell cancer 1483 cells. The treatment also leads to significant down-modulation of activated AKT and extracellular signal-regulated kinase in the cells, suggesting that critically diminished strength of these growth signals may be the key attributes of the induction of cell death. Furthermore, silencing the RHBDF1 gene in MDA-MB-435 or 1483 xenograft tumors on athymic nude mice by using i.v. administered histidine-lysine polymer nanoparticle-encapsulated siRNA results in marked inhibition of tumor growth. Our findings indicate that RHBDF1 has a pivotal role in sustaining growth signals in epithelial cancer cells and thus may serve as a therapeutic target for treating epithelial cancers. [Mol Cancer Ther 2008;7(6):1355–64]</p></div>

10.1158/1535-7163.c.6531672.v1

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Rational Design of a Humanized Glucagon‐Like Peptide‐1 Receptor Agonist Antibody

Angewandte Chemie (2014)

Yong Zhang Huafei Zou Ying Wang Dawna Caballero J. González

Abstract Bovine antibody BLV1H12 possesses a unique “stalk–knob” architecture in its ultralong heavy chain CDR3, allowing substitutions of the “knob” domain with protein agonists to generate functional antibody chimeras. We have generated a humanized glucagon‐like peptide‐1 (GLP‐1) receptor agonist antibody by first introducing a coiled‐coil “stalk” into CDR3H of the antibody herceptin. Exendin‐4 (Ex‐4), a GLP‐1 receptor agonist, was then fused to the engineered stalk with flexible linkers, and a Factor Xa cleavage site was inserted immediately in front of Ex‐4 to allow release of the N‐terminus of the fused peptide. The resulting clipped herceptin–Ex‐4 fusion protein is more potent in vitro in activating GLP‐1 receptors than the Ex‐4 peptide. The clipped herceptin–Ex‐4 has an extended plasma half‐life of approximately four days and sustained control of blood glucose levels for more than a week in mice. This work provides a novel approach to the development of human or humanized agonist antibodies as therapeutics.

Ex vivo

10.1002/ange.201410049

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Citations (4)

Interaction of Caveolin-1 with Ku70 Inhibits Bax-Mediated Apoptosis

PLoS ONE (2012)

Huafei Zou Daniela Volonté Ferruccio Galbiati

Caveolin-1, the structural protein component of caveolae, acts as a scaffolding protein that functionally regulates signaling molecules. We show that knockdown of caveolin-1 protein expression enhances chemotherapeutic drug-induced apoptosis and inhibits long-term survival of colon cancer cells. In vitro studies demonstrate that caveolin-1 is a novel Ku70-binding protein, as shown by the binding of the scaffolding domain of caveolin-1 (amino acids 82–101) to the caveolin-binding domain (CBD) of Ku70 (amino acids 471–478). Cell culture data show that caveolin-1 binds Ku70 after treatment with chemotherapeutic drugs. Mechanistically, we found that binding of caveolin-1 to Ku70 inhibits the chemotherapeutic drug-induced release of Bax from Ku70, activation of Bax, translocation of Bax to mitochondria and apoptosis. Potentiation of apoptosis by knockdown of caveolin-1 protein expression is greatly reduced in the absence of Bax expression. Finally, we found that overexpression of wild type Ku70, but not a mutant form of Ku70 that cannot bind to caveolin-1 (Ku70 Φ→A), limits the chemotherapeutic drug-induced Ku70/Bax dissociation and apoptosis. Thus, caveolin-1 acts as an anti-apoptotic protein in colon cancer cells by binding to Ku70 and inhibiting Bax-dependent cell death.

Ku70

Caveolin 1

10.1371/journal.pone.0039379

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Citations (24)

Rheb GTPase Controls Apoptosis by Regulating Interaction of FKBP38 with Bcl-2 and Bcl-XL

Journal of Biological Chemistry (2010)

Dongzhu Ma Xiaochun Bai Huafei Zou Yumei Lai Yu Jiang

RHEB

Small GTPase

10.1074/jbc.m109.092353

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Citations (46)