Fei Chen

Faculty Profile


Research Description

Primary Research Interest
Mdig gene and histone demethylation in lung cancer (1RO1ES017217-01A2)

Lung cancer is the most common cancer worldwide, accounting for 1.3 million cancer deaths annually. Despite extensive efforts to elucidate mechanisms and develop new therapeutic regimens, the worldwide mortality rate of lung cancer remains high. The objective of this project is to investigate the role of Mdig, a mineral dust-induced gene we identified from alveolar macrophages of patients with occupational lung diseases, played on lung cell proliferation and carcinogenic transformation induced by environmental and occupational hazards. The central hypothesis is that Mdig promotes cell growth and transformation by functioning as a histone demethylase that antagonizes tri-methyl lysine 9 on histone H3 (H3K9me3). Down-regulation of H3K9me3 will enhance the expression of genes associated with the cell cycle regulation and malignant transformation in lung epithelial cells. To accomplish the goal of this project, we will: (1) test the potential demethylase activity of mdig protein toward H3K9me3; (2) determine whether the expression of the cell cycle-regulated genes, such as cyclins, Cdc25s and checkpoint proteins, is regulated by the methylation regulation of mdig; and (3) study the tumorigenic effect of mdig by both over-expression and down-regulation of mdig in BEAS-2B cells and A549 cells, respectively, in both cell culture and inoculation of the cells in nude mice. At the completion of this project, it is anticipated that in addition to reveal a previously unknown new mechanism of the human lung cancer, the expression of mdig can be potentially served as a new biomarker and therapeutic target of the human lung cancer.

Secondary Research Interest
Arsenic-induced alternative splicing of the GADD45a in carcinogenesis

Environmental arsenic exposure, especially the trivalent form arsenic (As3+), has long been known to be a risk factor for human cancers, including cancers of lung, liver, skin, kidney, and urinary bladder. Despite extensive efforts to elucidate how As3+ causes human cancer, the underlying mechanism remains to be investigated. Our previous studies have shown that (a) As3+ is able to generate reactive oxygen species (ROS) and induces GADD45a, a tumor suppressor protein; (b) As3+ causes alternatively splicing of the GADD45a mRNA to generate a short version of the GADD45a (sG45a) isoform, leading to un-controlled cell growth or disruption of cell growth arrest at G2/M phase; (c) As3+-induced sG45a also inhibits the function of the GADD45a by inhibiting interaction of the GADD45a with CDC2/cyclin B complex; (d) Overexpression of the As3+-induced sG45a can induce cell transformation. Thus, we hypothesize that As3+- induces oxidative stress and causes generation of sG45a, leading to inhibition of GADD45a, disruption of cell growth control, and consequently, the cell transformation and carcinogenesis. Accordingly, we will investigate: (1) how As3+ induces ROS generation with emphasis on the role of NADPH oxidase in human bronchial epithelial cell line, BEAS-2B; (2) how As3+ or its induced ROS affect the assembly of the spliceosome machinery that causes alternative splicing of GADD45a pre-mRNA for the generation of sG45a; (3) the role sG45a in As3+-induced carcinogenesis by overexpression of the sG45a in human bronchial epithelial cells. We will establish stable transfectants and determine the effects of overexpression of sG45a on either basal or As3+-induced cell transformation and carcinogenesis by assays of colony formation in soft agar (anchorage independence) and inoculation of the cells in nude mice. The completion of this project will establish new mechanisms of As3+-induced carcinogenesis in human.

Third Research Interest
JNK1 and EZH2 in hepatocellular carcinoma

In the United States, hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related death in men from 1975 to present, despite the fact that the overall cancer mortality rate has declined at the same period. Tremendous efforts to diagnose and institute new treatment regimens have been made in recent years. However, the prognosis of HCC is still extremely poor. Recently, we and others have revealed an important role for c-Jun N-terminal kinase 1 (JNK1) in the pathogenesis of human HCC and its close association with the expression of HCC signature genes. The long-term goal of this project is to develop an innovative HCC treatment regimen based on molecular targeting to JNK1. We hypothesize that the tumor promoting activity of JNK1 in HCC is achieved by directly regulating genes, such as EZH2 and cyclins, that alter the epigenetic landscape of the genome and the transformational potential of the hepatocytes. To test this hypothesis, we will: 1), determine the regulatory role of JNK1 on EZH2 expression and assess the molecular determinants responsible for JNK1 activity on the transcription of EZH2 in hepatocytes and HCC. a), test the hypothesis that JNK1 induces EZH2 through transcriptional regulation of the Ezh2 gene; b), determine whether HCC patients can be stratified based on both JNK1 activation status and the EZH2 expression level; 2), characterize the regulatory role of JNK1 on EZH2 as a key part of its effect on cell cycle control and determine whether the effects of JNK1 on cell cycle are EZH2 dependent in the development of HCC; and 3), test the tumorigenic effect of JNK1 and EZH2 in mouse HCC model: a), tumorigenicity assay using HCC cells in which JNK1 or EZH2 is silenced by shRNA through inoculation of the cells in nude mice; b), using wild-type and JNK1 knockout mice to test the role of JNK1 in liver carcinogenesis in vivo in diethylnitrosamine (DEN)-induced HCC model; and c), investigate therapeutic potential of JNK1 inhibitors for HCC in wild-type mice treated with hepatic carcinogen. At the completion of this project, we expect to have determined the role of JNK1 in the pathogenesis and prognosis of HCC. Based on preliminary studies, we believe that sustained activation of JNK1 is the key for the alteration of epigenetics and genes that cause malignant transformation of the hepatocytes. Furthermore, in addition to reveal a previously understudied role of JNK1 in HCC pathogenesis, it is anticipated that JNK1 activation can potentially serve as a novel therapeutic target.

Affiliated Departments