EPIGENETICS AND HISTONE UBIQUITINATION IN OVARIAN CANCER

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Degree type
Doctor of Philosophy (PhD)
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Cell and Molecular Biology
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Biology
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Biology
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2023
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Ferrari, Adam , J
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Abstract

Ovarian cancer has the highest mortality rates of all gynecologic cancers. Epithelial ovarian cancers (EOC), accounting for 90% of all ovarian tumors, includes a number of histotypes. Each histotype is morphologically distinct, exhibits unique molecular features, and responds to therapy differently. High grade serous ovarian carcinoma (HGSOC) is the most common histotype of EOC. Unfortunately, it is typically detected at advanced stages and has a 5-year survival rate of less than 30%. A less common subtype but no less formidable is clear cell ovarian cancer (CCOC). This subtype, when detected late, has a response rate to standard therapy of less than 10%, and when it recurs, the response rate drops to less than 1%. These dismal statistics are in part attributable to a poor understanding of the factors that underlie neoplastic transformation. Efforts to understand early events in HGSOC and CCOC remain an unmet clinical need. Recent advances show that HGSOC originates from the fallopian tube secretory epithelium cells (FTSEC). Transformation of FTSEC leads to development of a HGSOC precursor lesion called serous tubal intra-epithelial carcinoma (STIC). CCOC originates from endometriosis through an intermediate stage, atypical endometriosis. Molecular events within STIC and endometriotic lesions are driven by genetic and epigenetic alterations that confer survival advantages to nascent tumor cells and impact the local tumor microenvironment to promote disease progression. One epigenetic mark that is frequently lost in HGSOC is the monoubiquitination of histone H2B (H2Bub1). H2Bub1 plays important roles in DNA repair, transcription, and stem cell differentiation. Its loss in STIC lesions indicates that it is an early event in HGSOC. By immunohistochemistry of patient samples, we determined that H2Bub1 loss is profound in CCOC and in early events of disease progression. Genome-wide DNA methylation profiles of 230 CCOC patients identified hypermethylation of the primary E3 ligases RNF20 and RNF40 potentially explaining the loss of H2Bub1 in CCOC. We demonstrate that H2Bub1 depletion promotes cell proliferation and clonogenicity in an endometriosis cell line. Moreover, we determined that H2Bub1 loss in HGSOC may be a result of deubiquitinase activity which may include USP22 and other members of the SAGA complex. Finally, we show that H2Bub1 loss in HGSOC influences the immune microenvironment and progenitor cell characteristics. These results indicate that H2Bub1 plays a tumor suppressive role in both HGSOC and CCOC progression.

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Drapkin, Ronny
Date of degree
2023
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