Romi Gupta

Title : DOT1L promotes Ovarian Cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis

Abstract:

Ovarian cancer is the leading cause of gynecological malignancy-related deaths. Current therapies for ovarian cancer do not provide meaningful and sustainable clinical benefits, highlighting the need for new therapies. We show that the histone H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is overexpressed in ovarian cancer and that a higher level of DOT1L expression correlates with shorter progression-free and overall survival (OS). Pharmacological inhibition of DOT1L (EPZ-5676, EPZ004777, and SGC0946) or genetic inhibition of DOT1L attenuates the growth of ovarian cancer cells in cell culture and in a mouse xenograft model of ovarian cancer. Transcriptome-wide mRNA expression profiling shows that DOT1L inhibition results in the downregulation of genes involved in cellular biosynthesis pathways and the upregulation of proapoptotic genes. Consistent with the results of transcriptome analysis, the unbiased large-scale metabolomic analysis showed reduced levels of several metabolites of the amino acid and nucleotide biosynthesis pathways after DOT1L inhibition. DOT1L inhibition also resulted in the upregulation of the NKG2D ligand ULBP1 and subsequent increase in natural killer (NK) cell-mediated ovarian cancer eradication. Collectively, our results demonstrate that DOT1L promotes ovarian cancer tumor growth by regulating apoptotic and metabolic pathways as well as NK cell- mediated eradication of ovarian cancer and identifies DOT1L as a new pharmacological target for ovarian cancer therapy.

Biography:

Dr. Gupta did her BS and MS in India. She then joined Prof. Knud Nierhaus group at Max Planck Institute for Molecular Genetics, Berlin, Germany for her PhD and obtained her degree in the area of ribosome biology and protein translation. After that she worked at Yale University as postdoc where she extensively performed studies to identify new regulator in cancer growth and progression. Many of her studies are published in journals like eLife, PNAS, Cell Reports, Oncogene etc. Currently she is an Assistant Professor in the UAB and Associate scientist at O'Neal Comprehensive Cancer Center at UAB. Her lab Our works on identifying new molecules and pathways and studying their role in tumor initiation and progression. Her long-term goal is to not only identify new molecules and signaling pathways that regulate the disease but also develop more effective and durable cancer therapies.