Arsenic is a well-documented human carcinogen. Our goal is to address the central hypothesis that phosphorylation of histones and their upstream kinases play an important functional role in arsenic-induced cell transformation and carcinogenesis.
Specific Aim 1 is to study the role of histone phosphorylation in arsenic-induced cell transformation;
Specific Aim 2 is to investigate and identify the histone kinases that phosphorylate histone H3 and H2B at different amino acid residues;
Specific Aim 3 is to study the crystal structure of histone kinase RSK2, perform in- silico screening and design RSK2 inhibitors for suppressing arsenic-induced histone phosphorylation and cell transformation;
and Specific Aim 4 is to study the role of RSK2 in arsenic/ultraviolet A (UVA)-induced skin carcinogenesis and determine RSK2's potential as a target for chemoprevention of cancer. The strategy for Specific Aim 1 is to use point mutations at key phosphorylation sites of histone H3 and H2B siRNA gene knockdown and overexpressing stable cell lines to test the role of H3 and H2B in soft agar cell transformation assays.
For Specific Aim 2, we will use in vitro kinase assays, specific mutations, LTQ Orbitrap hybrid mass spectrometer analysis and RSK2 knockout cells as well as inhibitors of RSK2.
In Specific Aim 3, we will use x-ray crystallography to determine the structure of RSK2. Then we will use a super computer to screen a database of 2.5 million chemicals to find inhibitors for RSK2 to be tested in an in vitro kinase assay.
In Specific Aim 4, we will test the effect of the RSK2 inhibitor kaempferol and RSK2 knockout mice in UVA/arsenic-induced mouse skin carcinogenesis. Such knowledge will facilitate the design of more effective and specific strategies with fewer side effects for chemoprevention of arsenic- induced cancer.
Environmental arsenic contamination is a major problem in many parts of the world and is a well-documented human carcinogen. By using state-of-the-art technology such as x-ray crystallography, super computer based molecular modeling and drug screen, cellular and molecular biology and gene knockout mice, we will study the novel mechanism involved in histone phosphorylation on arsenic-induced cell transformation to cancer and the carcinogenesis process. These studies will facilitate the development of more effective agents with fewer side effects for chemoprevention against environmental carcinogens such as arsenicinduced cancer.
|Liu, Kangdong; Park, Chanmi; Chen, Hanyong et al. (2015) Eupafolin suppresses prostate cancer by targeting phosphatidylinositol 3-kinase-mediated Akt signaling. Mol Carcinog 54:751-60|
|Bode, Ann M; Dong, Zigang (2015) Toxic phytochemicals and their potential risks for human cancer. Cancer Prev Res (Phila) 8:8-Jan|
|Yang, Ge; Fu, Yang; Malakhova, Margarita et al. (2014) Caffeic acid directly targets ERK1/2 to attenuate solar UV-induced skin carcinogenesis. Cancer Prev Res (Phila) 7:1056-66|
|Sheng, Yuqiao; Li, Wei; Zhu, Feng et al. (2014) 3,6,2',4',5'-Pentahydroxyflavone, an orally bioavailable multiple protein kinase inhibitor, overcomes gefitinib resistance in non-small cell lung cancer. J Biol Chem 289:28192-201|
|Fu, Y; Yang, G; Zhu, F et al. (2014) Antioxidants decrease the apoptotic effect of 5-Fu in colon cancer by regulating Src-dependent caspase-7 phosphorylation. Cell Death Dis 5:e983|
|Liu, Haidan; Hwang, Joonsung; Li, Wei et al. (2014) A derivative of chrysin suppresses two-stage skin carcinogenesis by inhibiting mitogen- and stress-activated kinase 1. Cancer Prev Res (Phila) 7:74-85|
|Lim, Tae-Gyu; Lee, Sung-Young; Huang, Zunnan et al. (2014) Curcumin suppresses proliferation of colon cancer cells by targeting CDK2. Cancer Prev Res (Phila) 7:466-74|
|Wen, W; Peng, C; Kim, M O et al. (2014) Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability. Oncogene 33:421-8|
|Lim, Do Young; Lee, Mee-Hyun; Shin, Seung Ho et al. (2014) (+)-2-(1-Hydroxyl-4-oxocyclohexyl) ethyl caffeate suppresses solar UV-induced skin carcinogenesis by targeting PI3K, ERK1/2, and p38. Cancer Prev Res (Phila) 7:856-65|
|Yao, Ke; Chen, Hanyong; Liu, Kangdong et al. (2014) Kaempferol targets RSK2 and MSK1 to suppress UV radiation-induced skin cancer. Cancer Prev Res (Phila) 7:958-67|
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