Research
Cancer Research
We define cancer as a disease of gene networks gone awry. Our research focuses on the molecular mechanisms by which cancer-relevant genes regulate the networks in which they are embedded.
We believe that this type of basic research is a step in the development of effective cancer therapeutics. This field is broad with many important questions, which inspires us to constantly expand our repertoire of approaches and technologies to find answers.
Our most recent endeavor is the development of an in-lab bioinformatics practice that allows us to rapidly transition from the computational analysis of genomics data to hypothesis-driven experiments at the bench. We are currently developing the animal models necessary to test the hypothesis generated by our cell-based experiments at the organism level.
Dr. Espinosa is a Professor of Pharmacology, Director of the Functional Genomics Facility in the University of Colorado Cancer Center and the Espinosa Lab partners closely with numerous Cancer Center teams.
Featured Publications
In this review, the team focuses on recent advances in our understanding of mechanisms of p53-dependent transcriptional control as they relate to five key areas: (1) the functionally distinct N-terminal transactivation domains, (2) the diverse regulatory roles of its C-terminal domain, (3) evidence that p53 is solely a direct transcriptional activator, not a direct repressor, (4) the ability of p53 to recognize many of its enhancers across diverse chromatin environments, and (5) mechanisms that modify the p53-dependent transcriptional program in a context-dependent manner.
This publication describes a transcriptional mechanism that connects autophagy to apoptosis. The autophagy-regulating transcription factor, FOXO3a, is itself turned over by basal autophagy creating a potential feedback loop. Increased FOXO3a upon autophagy inhibition stimulates transcription of the pro-apoptotic BBC3/PUMA gene to cause apoptosis sensitization. This mechanism explains how autophagy inhibition can sensitize tumor cells to chemotherapy drugs and allows an autophagy inhibitor to change the action of an MDM2-targeted drug from growth inhibition to apoptosis, reducing tumor burden in vivo. Thus, a link between two processes mediated via a single transcription factor binding site in the genome can be leveraged to improve anti-cancer therapies.
This publication reports that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.