Nuclear protein kinase C- theta (PKC-θ) directly regulates inducible genes of epithelial to mesenchymal transition and breast cancer stem cells

Abstract

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	2016
Original language	English
Supervisor	Sudha Rao (Supervisor), Reena GHILDYAL (Supervisor), Anjum Zafar (Supervisor), Marco Casarotto (Supervisor), Kris Hardy (Supervisor) & Frances Shannon (Supervisor)