DOT1L gene was found to play a key role in progression and severity of ovarian cancer, said researchers. The inhibitors of the DOT1L enzyme may offer a new therapeutic approach for the disease, University of Alabama at Birmingham //researchers say in a study published in the journal Oncogenesis.
‘The histone methyltransferase DOT1L — the potential target — is overexpressed in ovarian cancer, and high levels of expression correlate with reduced progression-free and overall survival.’
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The need is clear — despite decades of work to develop new treatment modalities, the five-year survival of patients with advanced ovarian cancer is between 10 and 30 percent. Others have found that DOT1L is overexpressed in several cancer types, and recent clinical work has shown synergistic antiproliferative activity for a DOT1L inhibitor against MLL-rearranged leukemia.
The UAB researchers, led by Romi Gupta, Ph.D., assistant professor of biochemistry and molecular genetics, now show that DOT1L promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking the programmed cell death called apoptosis.
Gupta and colleagues first looked at data sets from patients. They found that DOT1L expression was significantly higher in tissues from ovarian cancer patients compared with tissues from healthy patients. Furthermore, patients with ovarian tumors that had high DOT1L expression showed shorter progression-free survival and shorter overall survival rates compared with patients whose ovarian tumors had lower DOT1L expression.
DOT1L is a histone methyltransferase that epigenetically methylates the histone H3 lysine 79 in chromatin, and this alters gene expression in cells. The UAB researchers found that EPZ-5676 — a DOT1L inhibitor that has been used in several clinical trials to treat MLL-rearranged leukemia — was able to block the growth of ovarian cancer cells in culture. EPZ-5676 also significantly blocked subcutaneous ovarian cancer tumor growth in a mouse xenograft model.
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These gene expression changes seen in DOT1L inhibitor-treated cells thus suggest that DOT1L overexpression in ovarian cancer leads to plentiful supplies of the metabolites needed for rapid tumor growth and also protects against tumor cell death caused by apoptosis or natural killer cell attack.
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Co-authors with Gupta for the study, “Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis,” are Suresh Chava, Suresh Bugide and Yvonne J.K. Edwards, UAB Department of Biochemistry and Molecular Genetics.
Source-Eurekalert