ZNF217 promotes ovarian cancer progression through cancer cell intrinsic and extrinsic mechanisms

Abstract

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecological malignancy in the United States. Due to the absence of a reliable early diagnostic biomarker and the vague presentation of early clinical symptoms, most women will receive a diagnosis in a metastatic stage of disease progression. At this point, the efficacy of extant therapeutic strategies drops significantly, resulting in disappointing 5-year survival outcomes of less than 30%. This unfortunate clinical reality highlights the urgent need to identify new drug targets and more effective therapeutic strategies to treat metastatic ovarian cancer. Achieving this goal has proved challenging, largely due to the knowledge gap in our understanding of factors that drive metastasis and drug resistance in ovarian cancer. For these reasons, my thesis project has focused on identifying factors that contribute to ovarian carcinogenesis with the goal of identifying new molecular targets for the development of more efficacious therapeutic strategies. One such emergent molecular target is the transcription factor, Zinc Finger Protein 217 (ZNF217). The genomic locus harboring ZNF217 (20q13.2) is frequently amplified in many human cancers, including ovarian cancer. Consistently, ZNF217 mRNA is elevated in ovarian tumors. Importantly, elevated ZNF217 mRNA levels were found to correlate with poor clinical outcome in ovarian cancer patients. Despite this compelling link, very little is known about the role of ZNF217 in ovarian cancer pathogenesis. To address this critical knowledge gap, my thesis project focused on understanding the role of ZNF217 in ovarian carcinogenesis. Using clinically relevant in vitro as well as in vivo models, I establish that ZNF217 functions as a potent oncogene that promotes cell proliferation, epithelial-to-mesenchymal transition (EMT), metastasis, and chemoresistance in ovarian cancer cells. I show that ZNF217’s ability to drive these oncogenic phenotypes is dependent upon its ability to bind DNA and alter the expression of its downstream target genes. Interestingly, I discovered that ZNF217 co-operates with estrogen to promote metastatic phenotypes in ovarian cancer cells. These data underscore the critical role elevated ZNF217 may play in estrogen receptor-positive ovarian cancers. In addition to this, I show that ZNF217 overexpression impacts the expression of various cytokines and chemokines that are known to facilitate an immune-suppressive tumor microenvironment. These data suggest that ZNF217 overexpression could potentially impact the ovarian tumor microenvironment and the response of ovarian cancer cells to immunotherapy. Finally, my work demonstrates that ZNF217 stability is influenced by glucose availability in the microenvironment. Glucose deprivation caused ZNF217 depletion in cells and this effect was phenocopied by small molecules that activate the AMP-activated protein kinase (AMPK), an enzyme that regulates cellular energy levels. These data suggest that the effect of glucose on ZNF217 is likely mediated via the AMPK pathway. Taken together, my work shows that ZNF217 impacts ovarian cancer progression through both cancer cell intrinsic as well as extrinsic mechanisms. By establishing ZNF217 as a critical factor driving ovarian cancer progression and metastasis and identifying potential pathways that regulate ZNF217 levels in ovarian cancer cells, this thesis has laid groundwork to investigate ZNF217’s utility as a therapeutic target in metastatic ovarian tumors.