G9a/EHMT2 Methyltransferase Activity Controls Stem-Like Identity and Tumor-Initiating Function in Human Colorectal Cancer

Title: G9a/EHMT2 Methyltransferase Activity Controls Stem-Like Identity and Tumor-Initiating Function in Human Colorectal Cancer
Authors: Zouggar, Aïcha
Date: 2021-02-23
Abstract: Colorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of a cancer stem-like phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in developing and maintaining cancer stem cells by establishing embryonic stem-like transcriptional programs, thus altering the balance between self-renewal and differentiation. Through my work, I have identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, I demonstrate that G9a activity is essential for the maintenance of an embryonic stem-like transcriptional signature that is required to promote self-renewal, tumorigenicity and an undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. By integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, the canonical Wnt pathway, epithelial-to-mesenchyme transition and extracellular matrix organization were identified as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Considering such novel insights on the role of G9a as a driver of the cancer stem cell phenotype, as well as a promoter of self-renewal, tumorigenicity and an undifferentiated state, I established and executed a multi-step drug screening pipeline to identify new repurposed drugs that selectively alter G9a functions in human CSCs. This pipeline revealed 3 new drug candidates that inhibit H3K9me2 deposition and impair human CSCs in culture. Future in-depth characterization of those candidates will represent an important step toward the development of novel CSC-targeting therapeutics.
URL: http://hdl.handle.net/10393/41821
CollectionThèses, 2011 - // Theses, 2011 -