Agents for reversing epigenetic silencing of genes
The present invention provides methods for discovering agents that are effective in reversing epigenetic silencing by inhibiting the interaction of methyl-binding (MBD) proteins with methylated genomic DNA. Also provided are methods for reactivating silenced genes having CpG island hypermethylation along with methods for treatment and prevention of diseases, such as cancer and sickle cell anemia, by administering an agent that modulates methyl-binding domain (MBD) protein-mediated transcriptional repression, thereby increasing gene transcription to prevent or treat disease. Additionally, compounds identified by the present invention useful for treatment and prevention of diseases, such as cancer and sickle cell anemia, are provided.
1. A method of treating cancer in a subject having CpG island hypermethylation of a GSTP1 gene comprising administering to the subject an agent that modulates methyl-binding domain (MBD) protein-mediated transcriptional repression,
wherein the agent is a chemical compound of Formula II
and
wherein the cancer is prostate cancer, thereby increasing transcription of the GSTP1 gene and thereby treating the cancer.
2. The method of claim 1 , wherein the MBD protein is MBD2.
3. The method of claim 1 , wherein the agent inhibits interaction of a methyl-binding domain (MBD) protein with methylated genomic DNA.
4. The method of claim 1 , wherein the subject is a human.
5. The method of claim 1 , wherein the MBD protein is MeCP2.
6. A method of treating proliferation or metastasis of a cancer cell in a subject having CpG island hypermethylation of a GSTP1 gene comprising administering to the subject an agent that modulates methyl-binding domain (MBD) protein-mediated transcriptional repression,
wherein the agent is a chemical compound of Formula II
and
wherein the cancer cell is prostate cancer cell,
thereby increasing transcription of the GSTP1 gene and thereby treating the proliferation or metastasis of the cancer cell.