RESUMO
A few recent reports reveal fundamental new insights into the intricate regulatory mechanisms that govern RNA polymerase II (Pol II)-mediated gene transcription. Whereas a histidine-rich domain (HRD) triggers phase separation, promoting transcription elongation, a phosphatase switch promotes transcription termination. A paradigm that might govern the underlying mechanisms leading to robust gene transcription is now starting to emerge.
Assuntos
Cromatina/genética , Processamento de Proteína Pós-Traducional/genética , RNA Polimerase II/genética , Transcrição Gênica , Humanos , Monoéster Fosfórico Hidrolases/genética , Fosforilação , Fator B de Elongação Transcricional Positiva/genética , Fatores de Transcrição/genéticaRESUMO
Chromatin modifications have gained immense significance in the past few decades as key regulators of gene expression. The enzymes responsible for these modifications along with the other non-histone proteins, remodeling factors and small RNAs modulate the chromatin dynamicity, which in turn directs the chromatin function. A concerted action of different modifying enzymes catalyzes these modifications, which are read by effector modules and converted to functional outcomes by various protein complexes. Several small molecules in the physiological system such as acetyl CoA, NAD(+), and ATP are actively involved in regulating these functional outcomes. Recent understanding in the field of epigenetics indicate the possibility of the existence of a network, 'the epigenetic language' involving cross talk among different modifications that could regulate cellular processes like transcription, replication and repair. Hence, these modifications are essential for the cellular homeostasis, and any alteration in this balance leads to a pathophysiological condition or disease manifestation. Therefore, it is becoming more evident that modulators of these modifying enzymes could be an attractive therapeutic strategy, popularly referred to as 'Epigenetic therapy.' Although this field is currently monopolized by DNA methylation and histone deacetylase inhibitors, this review highlights the modulators of the other modifications namely histone acetylation, lysine methylation and arginine methylation and argues in favor of their therapeutic potential.
Assuntos
Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Histonas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Acetilcoenzima A/química , Acetilcoenzima A/metabolismo , Acetilação/efeitos dos fármacos , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Cromatina/química , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Ativadores de Enzimas/química , Ativadores de Enzimas/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Histonas/química , Humanos , Metilação/efeitos dos fármacos , NAD/química , NAD/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
Altered histone acetylation is associated with several diseases, including cancer. We report here that, unlike in most cancers, histones are found to be highly hyperacetylated in oral squamous cell carcinoma (OSCC; oral cancer) patient samples. Mechanistically, overexpression, as well as enhanced autoacetylation, of p300 induced by nucleophosmin (NPM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) causes the hyperacetylation, which is nitric oxide (NO) signal dependent. Inhibition of the histone acetyltransferase (HAT) activity of p300 by a water-soluble, small molecule inhibitor, Hydrazinocurcumin (CTK7A), substantially reduced the xenografted oral tumor growth in mice. These results, therefore, not only establish an epigenetic target for oral cancer, but also implicate a HAT inhibitor (HATi) as a potential therapeutic molecule.
