Discovery Pinpoints How Some Aggressive Cancers Turn Off Tumor Suppressor Genes

Charles Brenner, PhD Roy J. Carver Chair & Head of Biochemistry Departments of Biochemistry & Internal Medicine Carver College of Medicine University of Iowa Iowa City, IA  52242MedicalResearch.com Interview with:
Charles Brenner, PhD

Roy J. Carver Chair & Head of Biochemistry
Departments of Biochemistry & Internal Medicine
Carver College of Medicine
University of Iowa Iowa City, IA  52242

Medical Research: What is the background for this study? What are the main findings?

Dr. Brenner: KRAS mutations are extremely common in human malignancies. The KRAS gene is an oncogene that drives cell growth pathways and that leads to silencing and inactivation of tumor suppressor genes. It was known that KRAS mutant cancer cells silence tumor suppressor genes but the precise mechanism for gene silencing was not known. In this study, we discovered that KRAS mutations turn off the TET1 gene. TET1 functions as an “eraser” of gene silencing marks. When KRAS mutations occur, the TET1 eraser isn’t expressed any longer, and a series of tumor suppressor genes become silenced. This is an essential part of the aggressiveness of KRAS-dependent cancers and is controlled by the ERK pathway that is turned on by KRAS. In short, KRAS turns on ERK, which turns off TET1. When TET1 is off, a set of tumor suppressor genes are also turned off, which drives cancer formation.

Medical Research: What should clinicians and patients take away from your report?

Dr. Brenner: If genes such as EGFR, KRAS or BRAF are activated in cancer, ERK pathway inhibition might restore TET1 gene expression and consequent tumor suppressor gene function.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Brenner: We plan to test whether human tumors with mutations in the KRAS pathway respond to ERK pathway inhibitors by increasing TET1 expression and reducing their aggressiveness.

Citation:

Suppression of TET1-Dependent DNA Demethylation Is Essential for KRAS-Mediated Transformation

Bo-Kuan Wu, Charles Brenner

DOI: http://dx.doi.org/10.1016/j.celrep.2014.10.063
CellReports Published Online: November 26, 2014