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Exploring Targets of TET2-Mediated Methylation Reprogramming as Potential Therapeutic Targets and Discriminators of Prostate Cancer Progression.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Exploring Targets of TET2-Mediated Methylation Reprogramming as Potential Therapeutic Targets and Discriminators of Prostate Cancer Progression./
作者:	Kamdar, Shivani Nainesh.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	318 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
Contained By:	Dissertations Abstracts International83-01B.
標題:	Health sciences. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28265239
ISBN:	9798522946197

Exploring Targets of TET2-Mediated Methylation Reprogramming as Potential Therapeutic Targets and Discriminators of Prostate Cancer Progression.
Kamdar, Shivani Nainesh.

Exploring Targets of TET2-Mediated Methylation Reprogramming as Potential Therapeutic Targets and Discriminators of Prostate Cancer Progression. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 318 p.

Source: Dissertations Abstracts International, Volume: 83-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2021.

This item must not be sold to any third party vendors.

Aberrant cytosine methylation is one of the most common alterations in cancer, with global hypomethylation and regional hypermethylation characterizing many different malignancies, including prostate cancer. In normal cells, master methylation regulators, the ten-eleven translocase (TET) family of enzymes, demethylate genes by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine. Although lowered expression of all three TETs is common in prostate cancer, TET2 in particular plays a central role through its interaction with - and repression by - the androgen receptor. Loss of TET2 is associated with decreased cancer-specific survival, while missense alterations of TET2 are linked to metastatic disease.In this thesis, genome-wide targets of TET2 were examined via integrative (hydroxy)methylation and expression analysis to first identify how locus-specific epigenetic patterns affect prostate cancer cells and phenotype. Subsequently, genes regulated by TET2 were assessed to determine their individual and combinatorial utility as potential tumor suppressors or oncogenic factors in disease. In contrast to the paradigm of universal hydroxymethylation loss in cancer, locus-specific intronic retention in genes related to basic cellular function and intergenic gain of hydroxymethylcytosine marks proximal to androgen-related genes was observed in 22Rv1 prostate cancer cell lines. CRISPR-Cas9 based TET2 knockout in prostate cells identified high-confidence genes specifically mediated by TET2 methylation reprogramming. Expression loss of three such genes - ASB2, NUDT10, and SRPX - or increased promoter methylation of NRG1 was significantly (p<0.05, log-rank test) correlated with shorter recurrence-free survival time in an independent prostate tumor tissue dataset. Similarly, a TET2-mediated mechanism for overexpression of the transcription factor and oncogene SOX4 was identified for the first time in cancer, showing the utility of TET2-target gene mining to identify novel markers of progression or potential therapeutic targets in disease. Random-forest modeling of both downregulated and upregulated gene targets identified a 38G model which exhibits significant additive utility (HR: 2.799, 95%CI 1.498-5.229) to high-risk CAPRA-S risk classification for identification of patients at increased risk of biochemical cancer recurrence following surgery.Overall, this work provides insight into the epigenetic regulation of prostate cancer pathways and how TET2 dysregulation affects gene expression, and highlights the potential of TET2-mediated methylation reprogramming targets to contribute to predictive disease modeling or therapeutic target identification.

ISBN: 9798522946197Subjects--Topical Terms:

3168359
Health sciences.
Subjects--Index Terms:

Biochemical recurrence

Exploring Targets of TET2-Mediated Methylation Reprogramming as Potential Therapeutic Targets and Discriminators of Prostate Cancer Progression.
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506 $a This item must not be sold to any third party vendors.
520 $a Aberrant cytosine methylation is one of the most common alterations in cancer, with global hypomethylation and regional hypermethylation characterizing many different malignancies, including prostate cancer. In normal cells, master methylation regulators, the ten-eleven translocase (TET) family of enzymes, demethylate genes by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine. Although lowered expression of all three TETs is common in prostate cancer, TET2 in particular plays a central role through its interaction with - and repression by - the androgen receptor. Loss of TET2 is associated with decreased cancer-specific survival, while missense alterations of TET2 are linked to metastatic disease.In this thesis, genome-wide targets of TET2 were examined via integrative (hydroxy)methylation and expression analysis to first identify how locus-specific epigenetic patterns affect prostate cancer cells and phenotype. Subsequently, genes regulated by TET2 were assessed to determine their individual and combinatorial utility as potential tumor suppressors or oncogenic factors in disease. In contrast to the paradigm of universal hydroxymethylation loss in cancer, locus-specific intronic retention in genes related to basic cellular function and intergenic gain of hydroxymethylcytosine marks proximal to androgen-related genes was observed in 22Rv1 prostate cancer cell lines. CRISPR-Cas9 based TET2 knockout in prostate cells identified high-confidence genes specifically mediated by TET2 methylation reprogramming. Expression loss of three such genes - ASB2, NUDT10, and SRPX - or increased promoter methylation of NRG1 was significantly (p<0.05, log-rank test) correlated with shorter recurrence-free survival time in an independent prostate tumor tissue dataset. Similarly, a TET2-mediated mechanism for overexpression of the transcription factor and oncogene SOX4 was identified for the first time in cancer, showing the utility of TET2-target gene mining to identify novel markers of progression or potential therapeutic targets in disease. Random-forest modeling of both downregulated and upregulated gene targets identified a 38G model which exhibits significant additive utility (HR: 2.799, 95%CI 1.498-5.229) to high-risk CAPRA-S risk classification for identification of patients at increased risk of biochemical cancer recurrence following surgery.Overall, this work provides insight into the epigenetic regulation of prostate cancer pathways and how TET2 dysregulation affects gene expression, and highlights the potential of TET2-mediated methylation reprogramming targets to contribute to predictive disease modeling or therapeutic target identification.
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