UC San Diego

While the dynamic crosstalk between cancer and immune cells within the tumor microenvironment have been extensively investigated, the mechanisms by which immune signaling drives alterations in the cancer cell transcriptome remain to be fully examined. Notably, cytokines such as TNF-α that are released by immune cells can serve as tumor promoting signals to trigger activation of pro-oncogenic networks by the master inflammatory regulator, NFκB. Importantly, tumor promoting properties of inflammation are further regulated by various genetic aberrations in cancer cells. Of special interest are gain-of-function (GOF) mutations in the tumor suppressor gene, p53 which occur in approximately 50% of all human cancers and have been established to promote inflammation-induced oncogenesis.

in this dissertation, I provide mechanistic insights into the various modes by which mutant p53 fuels proinflammatory gene expression programs in colon cancer cells. First, I established that mutant p53 and NFκB redirect each other’s binding to distinct subsets of distal regulatory elements, commonly referred to as enhancers in response to chronic TNF signaling. Notably, this co-occupancy by mutant p53 and NFκB results in activation of such pro-tumorigenic enhancers. I also found that mutant p53 regulates the enhancer occupancy of the RNA polymerase II machinery and supports the biogenesis of nascent transcripts known as enhancer RNAs (eRNAs). Importantly, this pro-inflammatory eRNA signature was dependent on mutant p53 and not detected in cancer cell lines or human nonneoplastic tissues that expressed wild type p53.

Our group has since revealed the consequences of mutant p53-dependent eRNAs in gene regulation by establishing that these transcripts form complexes with the bromodomain and extra-terminal motif (BET) protein, BRD4 which often occupies active enhancers and regulates inflammatory and oncogenic programs. In this dissertation, I further explore the significance of transcriptional cofactors also functioning as noncanonical RNA binding proteins by establishing DNA topoisomerase 1 (TOP1) as an RNA interacting factor and demonstrating TOP1’s dependency on RNA associations to maintain its native protein interactome. Collectively, these findings define previously unrecognized mechanisms by which mutant p53 promotes inflammation-induced tumorigenesis through modulation of enhancer activity and underscore critical consequences of RNA-protein complexes.