Focusing on the Molecular Analysis of p53 Deregulation in Cancer Etiology and Progression
Over half of all human cancers consist of alterations in the p53 tumor suppressor gene. In normal healthy cells, p53 responds to stress stimuli by regulating the expression of downstream target genes that bring about various cellular outcomes (Fig.1). On the flip side of the coin, the regulation of these tumor suppressor genes is disrupted by mutations in p53, the vast majority of which are missense and localize to its DNA binding domain. Mutant p53 proteins (mutp53) lose tumor suppressor function and can also exhibit novel gain-of-function (GOF) activities that promote additional growth advantages over cells that lack p53. While mutp53 is an attractive target for cancer therapy, an understanding of the mechanisms underlying mutp53 regulation and function are needed before this oncogene can be exploited for therapeutic benefit. Toward this goal, I have developed a multidisciplinary research program to advance our understanding of the cellular and molecular mechanisms underlying the loss of function and GOF properties of mutp53. Our parallel lines of investigation aim to address the questions outlined below and ultimately promote human health through the identification of molecular vulnerabilities in mutp53 cancers that can serve as new biomarkers or therapies in precision medicine.
How do the complex interactions between immune signaling and mutp53 behavior lead to increased tumor aggressiveness and higher metastatic potential?
While inflammatory signaling influences cancer development and the efficacy of cancer treatments, the mechanisms by which immune signals drive alterations in the cancer cell transcriptome remain poorly understood. Moreover, the roles of mutp53 in modulating the immune contexture of tumors remain to be elucidated. The first key research theme of my lab is to identify the mechanisms regulating the complex crosstalk between mutp53 tumor and immune cells and the functional significance of these interactions in contributing to metastatic phenotypes.
How does mutp53 drive changes in chromatin-encoded epigenetic information and what is the role that these alterations play in carcinogenesis?
Research progress has been made in enumerating altered chromatin signatures and identifying mutations in the histone variant genes in various cancers. Yet, the molecular mechanisms underlying the establishment and functional consequences of altered chromatin states and histone variants in human cancers remain poorly understood. In addition, while numerous studies have linked the tumor suppressor activity of p53 to epigenome regulation, a link between mutp53 and epigenetic mechanisms has remained largely elusive. A second parallel line of investigation in my lab involves identification of the roles of histone variants and of mutp53 in imparting changes in the epigenome and transcriptome that are linked to alterations in cancer and immune cell behavior.
What noncoding RNA (ncRNA) signatures are regulated by mutp53 in different cancers and how are these ncRNAs regulated and function in human cancer?
The recent and intriguing discovery that enhancers support transcription has raised a key question of whether enhancer-derived RNAs (eRNAs) are functional, or merely reflections of enhancer activation and thereby transcriptional noise. Given the prevalence of eRNAs and that they are synthesized in a manner that correlates with the expression of nearby protein coding genes1-3, there is great potential for widespread regulation of gene expression by these ncRNAs. In addition, the recent identification of unique eRNA signatures in human cancer tissues is consistent with their potential in serving as therapeutic targets and biomarkers. However, the biggest barrier to moving these noncoding molecules to the clinic as the next generation of actionable targets is the significant lack of knowledge surrounding their biological roles. We have recently identified eRNAs that are robustly produced from a class of enhancers by mutp53 following chronic immune signaling4. Our functional assessment of these eRNAs has revealed their direct role in regulating tumor promoting gene activation5. Through a third and related line of investigation, my lab is at the forefront of uncovering new classes of eRNAs in various cancers and mechanistic insights into the functions of these noncoding transcripts in human cancers.