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Finding the 'off' switch
WEST LAFAYETTE, Ind.—Cancer is typified by cell mutation and uncontrolled replication, and given that stem cells have the ability to replicate repeatedly, some scientists have chosen to explore them as a possible source of answers on this disease.
Stem cells can replicate and produce new cells that then differentiate into somatic cells, “regular” cells such as skin, muscle or blood cells. However, sometimes the mechanisms that allow for stem cells' replication don't get turned off after the cells become somatic cells, which opens the door to unchecked replication and cancer.
Humaira Gowher, an associate professor in the Department of Biochemistry at Purdue University, and her team previously reported that normal embryonic stem cells differentiate and repress the genes for “stemness” by silencing control elements known as stem cell enhancers via DNA methylation. In DNA methylation, methyl groups to a select DNA segment, which then alters the DNA's activity. During this work, they identified the enzyme Lsd1 as playing a role in DNA methylation. If stemness genes are not fully repressed, it can result in partial differentiation in cancerous cells; in addition, enhancers can be reactivated to trigger renewed replication.
“If you differentiate normal stem cells, they should silence their pluripotency gene enhancers, but these cells are not doing that. They’re leaving the enhancer program partially open,” Gowher explained. “We’ve uncovered the issue that shelves these cells in some kind of intermediate, rather than in terminally differentiated, state.
“What people have seen in some cancers is that enhancers exist in a primed state. It can potentially help the cancer stem cells survive and propagate. It’s a pro-survival mechanism.”
In their most recent paper—“Oct4-Mediated Inhibition of Lsd1 Activity Promotes the Active and Primed State of Pluripotency Enhancers,” which appeared in Cell Reports—Gowher and her team looked at what other biological factors can affect Lsd1.
“Studies by the Cancer Genome Anatomy Project (CGAP) show that one out of three cancers express [pluripotency genes (PpG)], suggesting their role in dysregulated proliferation during tumorigenesis. Further, expression of PpGs, Oct4, Sox2, and Nanog potentiates self-renewal of putative cancer stem cells (CSCs),” the authors wrote. “CSCs proliferate as well as differentiate to give rise to cancer cells of various lineages. However, to retain the ability to proliferate, many cancer cells maintain expression of PpGs. This has led to the development of terminal differentiation therapy, which aims to limit the proliferating cancer cell population.”
A key focus in this study was the OCT4 protein. OCT4 is a stem cell transcription factor that inhibits the activity of Lsd1, which can lead to the incomplete deactivation of stem cell enhancers.
“Lsd1 was also shown to be present in the Oct4 interaction network, and therefore could be targeted to Oct4-bound regulatory elements, which largely control pluripotency and stemness … Taken together, our data show that inhibition of Lsd1 activity and Dnmt3a leads to the establishment of a “primed” enhancer state, which is open for coactivator binding and prone to reactivation. We speculate that aberrant expression of Oct4 in CSCs facilitates the establishment of “primed” enhancers, the reactivation of which supports tumorigenicity,” the authors reported.
“Because of this aberrant presence of OCT4, cells aren’t completely differentiating,” Gowher commented in a Purdue press release. “If you could inhibit the OCT4-Lsd1 interaction, or target degradation of OCT4, that should allow the cells to differentiate. That could be a target for a cancer therapy.”
That theory is one that Gowher's lab will be exploring as they further pursue this line of research. The scientists want to pinpoint exactly how Lsd1 and OCT4 interact, in addition to searching for other transcription factors that might also inhibit Lsd1.
Source: Purdue University press release