Abstract POSTER-BIOL-1324A: Loss of DYRK1A promotes transformation of the fallopian tube epithelial cells by oncogenic ras

Abstracts: 10th Biennial Ovarian Cancer Research Symposium; September 8-9, 2014; Seattle, WA Purpose of the study: High-grade serous ovarian carcinoma (HGSOC) is an aggressive form of ovarian cancer that is characterized by nearly ubiquitous presence of somatic mutations in TP53 gene and widespread gene copy number variations. It is likely that some of these genetic alterations cooperate with TP53 mutations in the pathogenesis of HGSOC; however, the specific roles of individual genes that are frequently gained or lost in HGSOC are only beginning to emerge. We have previously characterised an important role of DYRK1A protein kinase in the ability of human cells to undergo G0/G1 cell cycle arrest and oncogenic-Ras induced senescence. DYRK1A is required for the assembly of the DREAM repressor complex that controls the genes involved in cell cycle progression; this function of DYRK1A could be promoted by LATS kinases of the Hippo tumor suppressor pathway. Analysis of the The Cancer Genome Atlas (TCGA) ovarian dataset revealed loss of heterozygosity (LOH) of DYRK1A gene in over 25% HGSOC tumors. Therefore, we sought to determine whether loss of DYRK1A function can contribute to ovarian carcinogenesis. Experimental Procedures: A panel of human ovarian cancer cell lines was used to determine the levels of DYRK1A and its ability to suppress cell proliferation. The fallopian tube epithelial cell (FTEC) cell lines with stable shRNA knock-down of DYRK1A were used in transformation assays with ovarian cancer-relevant oncogenes. Bioinformatics analysis of the TGCA ovarian oncogenomic dataset was applied to determine whether DYRK1A loss in HGSOC could lead to perturbation of any specific gene expression programs. Summary of Data: It was found that depletion of DYRK1A promotes oncogenic transformation of the FTEC cells expressing mutant p53R175H and oncogenic HRASG12V. Rescue of DYRK1A expression in these cells resulted in arrest of proliferation and senescence. DYRK1A protein levels were reduced in a subset of ovarian cancer cell lines; overexpression of active but not the kinase-inactive DYRK1A suppressed the proliferation of these cells. Gene Set Enrichment Analysis (GSEA) of the TCGA HGSOC dataset revealed upregulated expression of the DREAM target genes in a subset of samples with LOH of both DYRK1A and LATS1 genes. Conclusion: Our findings support the role of DYRK1A as an ovarian tumor supressor and suggest that loss of DYRK1A function in HGSOC could lead to activation of transcription of the genes involved in cell proliferation. Citation Format: Larisa Litovchick, Siddharth Saini, Alison Karst, Lan Hu, Ronny Drapkin, James A. DeCaprio. Loss of DYRK1A promotes transformation of the fallopian tube epithelial cells by oncogenic ras [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1324A.