Investigation of regulation of promoter proximal pausing in YAP driven tumorigenesis

Abstract

Cancer is a multifaceted and diverse disease marked by unregulated cell division and expansion. These cancerous cells cause genetic alterations and enables hitching of signalling pathways and regulatory networks. The Hippo-YAP signaling pathway an evolutionarily conserved pathway that is involved in controlling organ size and development. Dysregulation of the Hippo-YAP pathway is associated with a large number of human cancers and there are multiple efforts to target key components of the pathway for disease intervention. The Hippo-YAP pathway has been implicated in several types of cancer, involving liver, lung, breast, and colon cancer. Downstream regulator of Hippo pathway – YAP (Yes-Associated Protein) acts as co-activator during transcription and that plays a vital role in regulating cellular growth, differentiation and proliferation, and which is a key effector in the pathway. In eukaryotes, RNA polymerase II (RNAPII) is responsible for the transcription of protein-coding genes as well as many non-coding genes. Among the three steps transcript elongation is discontinuous and can be perturbed by intrinsic regulatory barriers, such as promoter-proximal pausing (PPP), nucleosomes, secondary structures of RNA and the underlying DNA sequence. The temporary halting of RNA polymerase Ⅱ during the elongation phase is known as promoter-proximal pausing (PPP), regulated by a complex known as negative elongation factor (NELF). Previous work in the lab, discovered that PPP regulates tumorigenesis by regulating Yki transcription, we are investigating if PPP regulated YAP targets are crucial towards neoplastic transformation in mammalian cells as well. Here we explored effect of PPP mediated regulation of YAP target gene expression on breast cancer outcomes using TCGA and an Indian cohort of breast cancer patient samples. We further investigated mechanism of PPP in YAP transcription regulation using breast cancer cell lines.