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The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression / CARMEN TSE

Swansea University Author: CARMEN TSE

DOI (Published version): 10.23889/SUthesis.60060

Abstract

Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynaecological cancers globally. High-grade serous ovarian carcinomas (HGSOC) comprise 75% of EOCs and are characterised by diagnosis at advanced stages due to the late manifestation of non-specific symptoms. The majority of HGSOC...

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Published: Swansea 2022
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Cronin, James G. ; Francis, Lewis ; Johnson, Amy
URI: https://cronfa.swan.ac.uk/Record/cronfa60060
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spelling 2022-05-23T12:34:44.5060756 v2 60060 2022-05-23 The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression 4553a16233155a12bbbd77bc2f484f88 CARMEN TSE CARMEN TSE true false 2022-05-23 Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynaecological cancers globally. High-grade serous ovarian carcinomas (HGSOC) comprise 75% of EOCs and are characterised by diagnosis at advanced stages due to the late manifestation of non-specific symptoms. The majority of HGSOC cells are found to metastasise to the omentum, an adipocyte-rich membrane which can metabolise chemotherapeutic drugs. EOC patients develop malignant ascites, characterised by the high concentration of cytokines and the presence of multicellular aggregates of EOC cells known as spheroids. Both characteristics can facilitate EOC metastasis. EOC patients initially respond well to platinum-based chemotherapy, but the vast majority will relapse and eventually develop chemotherapy-resistant disease. Long-term survival for OC has shown no recent improvement which highlights the needs for new strategies that improve EOC prognosis. The dysregulation of the epigenetic landscape is a hallmark of EOC leading to the activation of oncogenes and suppression of anti-tumour genes. Ten-eleven translocation (TET) 2 is involved in DNA demethylation, playing a role in transcriptional regulation and gene expression. Oncometabolites present in EOC can inhibit TET2 which leads to aberrant gene regulation, contributing to malignant transformation and progression. Additionally, TET2 can be stabilised by metformin through activation of AMPK, a key regulator of cellular energy homeostasis. Metformin, a biguanide drug widely prescribed as first line treatment for diabetes, has shown promise as an anti-cancer drug. In EOC, metformin has been linked with an increased survival rate in addition to being able to decrease cytokine production and tumour formation in ovarian tumour cells. However, here metformin was found to increase cytokine (IL-6 and IL-8) production in chemosensitive EOC cells, under conditions of a physiological EOC tumour microenvironment (i.e., restricted glucose conditions), but not in chemoresistant EOC cells. This may be unfavourable if metformin was to be repurposed as treatment for EOC and may account for its inconsistent efficacy as a potential therapeutic drug in other cancers. Pathways including AMPK/TET2, and JAK/STAT were explored using techniques such as western Blot, Chromatin immunoprecipitation (ChIP) and methylated DNA immunoprecipitation (MeDIP) as possible mechanisms for this response. Cell viability and proliferation assays were used to explore the effect of oncometabolites on EOC cells. The results will provide insights into how metabolites affect EOC progression in addition to identifying potential therapeutic targets. E-Thesis Swansea Ovarian Cancer, Immunometabolism, Oncometabolites, Metformin, Epigenetics 19 5 2022 2022-05-19 10.23889/SUthesis.60060 COLLEGE NANME COLLEGE CODE Swansea University Cronin, James G. ; Francis, Lewis ; Johnson, Amy Doctoral Ph.D 2022-05-23T12:34:44.5060756 2022-05-23T12:16:25.7876636 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine CARMEN TSE 1 60060__24146__41120a75da4444ed9f94a67f0b7cc074.pdf Tse_Carmen_PhD_Thesis_Final_Cronfa.pdf 2022-05-23T12:29:17.2532977 Output 7827298 application/pdf E-Thesis – open access true Copyright: The author, Carmen Tse, 2022. true eng
title The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression
spellingShingle The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression
CARMEN TSE
title_short The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression
title_full The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression
title_fullStr The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression
title_full_unstemmed The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression
title_sort The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression
author_id_str_mv 4553a16233155a12bbbd77bc2f484f88
author_id_fullname_str_mv 4553a16233155a12bbbd77bc2f484f88_***_CARMEN TSE
author CARMEN TSE
author2 CARMEN TSE
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publishDate 2022
institution Swansea University
doi_str_mv 10.23889/SUthesis.60060
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynaecological cancers globally. High-grade serous ovarian carcinomas (HGSOC) comprise 75% of EOCs and are characterised by diagnosis at advanced stages due to the late manifestation of non-specific symptoms. The majority of HGSOC cells are found to metastasise to the omentum, an adipocyte-rich membrane which can metabolise chemotherapeutic drugs. EOC patients develop malignant ascites, characterised by the high concentration of cytokines and the presence of multicellular aggregates of EOC cells known as spheroids. Both characteristics can facilitate EOC metastasis. EOC patients initially respond well to platinum-based chemotherapy, but the vast majority will relapse and eventually develop chemotherapy-resistant disease. Long-term survival for OC has shown no recent improvement which highlights the needs for new strategies that improve EOC prognosis. The dysregulation of the epigenetic landscape is a hallmark of EOC leading to the activation of oncogenes and suppression of anti-tumour genes. Ten-eleven translocation (TET) 2 is involved in DNA demethylation, playing a role in transcriptional regulation and gene expression. Oncometabolites present in EOC can inhibit TET2 which leads to aberrant gene regulation, contributing to malignant transformation and progression. Additionally, TET2 can be stabilised by metformin through activation of AMPK, a key regulator of cellular energy homeostasis. Metformin, a biguanide drug widely prescribed as first line treatment for diabetes, has shown promise as an anti-cancer drug. In EOC, metformin has been linked with an increased survival rate in addition to being able to decrease cytokine production and tumour formation in ovarian tumour cells. However, here metformin was found to increase cytokine (IL-6 and IL-8) production in chemosensitive EOC cells, under conditions of a physiological EOC tumour microenvironment (i.e., restricted glucose conditions), but not in chemoresistant EOC cells. This may be unfavourable if metformin was to be repurposed as treatment for EOC and may account for its inconsistent efficacy as a potential therapeutic drug in other cancers. Pathways including AMPK/TET2, and JAK/STAT were explored using techniques such as western Blot, Chromatin immunoprecipitation (ChIP) and methylated DNA immunoprecipitation (MeDIP) as possible mechanisms for this response. Cell viability and proliferation assays were used to explore the effect of oncometabolites on EOC cells. The results will provide insights into how metabolites affect EOC progression in addition to identifying potential therapeutic targets.
published_date 2022-05-19T04:17:51Z
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