Epithelial to mesenchymal transition (EMT) is a key event in cancer progression and the process of metastasis that creates a reservoir for cancer stem cells (CSCs) and is associated with highly aggressive traits. CSCs play a vital role in metastasis, therapeutic resistance and relapse in breast cancer patients. Protein Kinase C theta (PKC-θ) is signal transduction kinase that has been implicated in inflammatory disorders, tumor progression, and metastasis has been recently linked to aggressive breast cancer. Rao lab has previously shown that PKC-θ can directly translocate to nucleus to regulate inducible immune responsive gene transcription and micro-RNAs that essential for effective immune response in T cells. Hence, it will be a crucial step to unravel the molecular role of PKC-θ in EMT and CSCs formation process. Using cancer biological and epigenetics analysis, we have shown that PKC-θ promotes EMT by directly tethering chromatin for mediating inducible genes via transforming growth factor beta (TGF-β) and the key inflammatory regulatory protein NF-kappa B. Chromatinized PKC-θ acts as an essential active transcription complex for establishing permissive chromatin state at signature EMT genes. Genome-wide analysis identifies a unique cohort of EMT inducible genes that are directly tethered to PKC-θ. Overall, PKC-θ plays an irreplaceable role in regulating inducible transcription programs that drive EMT and CSCs formation via cross-talking with chromatin, which provide a novel mechanism to target breast cancer using epigenetic therapy.
|Date of Award
|Sudha Rao (Supervisor), Reena Ghildyal (Supervisor), Anjum Zafar (Supervisor), Marco Casarotto (Supervisor), Kris Hardy (Supervisor) & Frances Shannon (Supervisor)