When cells are exposed to physical or chemical agents that damage DNA, deleterious effects can ensue, including mutation, cancer or death. However, mechanisms are available to repair the damage, stabilize the genome and neutralize harmful effects. During the previous funding period, focus was placed on understanding the role of human HRAD9 in processes that promote survival and genomic integrity after radiation or chemical exposure. Our studies indicate that this evolutionarily conserved gene has multiple functions needed for the cellular response to DNA damage, including cell cycle checkpoints, DNA repair and pro-apoptotic activities. Recently, we obtained evidence that HRAD9 has another important activity, which is one focus of this proposal. HRAD9 can, like p53, act as a sequence specific transcription factor. HRAD9 can bind p53 consensus sequences in the p21 promoter and cause transcription when overexpressed. In addition, we demonstrated that HRAD9 can bind the Cox-2 promoter and transactivate that gene as well. Furthermore, we show that HRAD9 is essential for the radiation induction in vivo of both p21 and Cox-2. Based on these and other functions of HRAD9, we also hypothesized a role for the encoded protein in carcinogenesis, and now provide evidence for a relationship between HRAD9 and specifically prostate cancer. These two novel HRAD9 activities, ability to regulate transcription and a role in prostate cancer, will be pursued by addressing the following two hypotheses: 1. HRAD9 is a sequence specific transcription factor that can regulate the cellular response to DNA damage by transactivation of a network of multiple downstream target genes, i.e., it controls a novel damage response regulon. Experimental aims concern structural requirements of the activity, and the identification and biological significance of inducible genes in the network. 2. HRAD9 is causally related to prostate cancer. Experiments are proposed to examine the function of HRAD9 in this type of cancer, in particular as an oncogene. The results of this study should better define the role of HRAD9 in the cellular response to DNA damage, as a novel regulator of DNA damage-inducible genes, and also elucidate the role of HRAD9 in carcinogenesis, specifically in prostate. As such, the findings focused on HRAD9 should impact on basic research as well as clinical arenas where DNA damaging agents are used for therapy and prostate cancer treatment is a concern. This proposal focuses on the role of Rad9 in regulating expression of other genes involved in controlling cell growth and maintaining stability of the genetic material. In addition, it concerns a detailed analysis of the function of Rad9 in prostate cancer. As such, this project is important since the results could impact on human health and lead to the development of novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA130536-17
Application #
8115777
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2007-09-28
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
17
Fiscal Year
2011
Total Cost
$349,988
Indirect Cost
Name
Columbia University (N.Y.)
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Broustas, Constantinos G; Hopkins, Kevin M; Panigrahi, Sunil K et al. (2018) RAD9A promotes metastatic phenotypes through transcriptional regulation of Anterior Gradient 2 (AGR2). Carcinogenesis :
Lieberman, Howard B; Rai, Alex J; Friedman, Richard A et al. (2018) Prostate cancer: unmet clinical needs and RAD9 as a candidate biomarker for patient management. Transl Cancer Res 7:S651-S661
Lieberman, Howard B; Panigrahi, Sunil K; Hopkins, Kevin M et al. (2017) p53 and RAD9, the DNA Damage Response, and Regulation of Transcription Networks. Radiat Res 187:424-432
Panigrahi, Sunil K; Hopkins, Kevin M; Lieberman, Howard B (2015) Regulation of NEIL1 protein abundance by RAD9 is important for efficient base excision repair. Nucleic Acids Res 43:4531-46
Broustas, Constantinos G; Lieberman, Howard B (2014) RAD9 enhances radioresistance of human prostate cancer cells through regulation of ITGB1 protein levels. Prostate 74:1359-70
Ghandhi, Shanaz A; Ponnaiya, Brian; Panigrahi, Sunil K et al. (2014) RAD9 deficiency enhances radiation induced bystander DNA damage and transcriptomal response. Radiat Oncol 9:206
Broustas, Constantinos G; Lieberman, Howard B (2014) DNA damage response genes and the development of cancer metastasis. Radiat Res 181:111-30
Vasileva, Ana; Hopkins, Kevin M; Wang, Xiangyuan et al. (2013) The DNA damage checkpoint protein RAD9A is essential for male meiosis in the mouse. J Cell Sci 126:3927-38
Cheng, Haiying; Zhang, Zhenfeng; Borczuk, Alain et al. (2013) PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells. Carcinogenesis 34:739-49
Broustas, Constantinos G; Zhu, Aiping; Lieberman, Howard B (2012) Rad9 protein contributes to prostate tumor progression by promoting cell migration and anoikis resistance. J Biol Chem 287:41324-33

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