Material Type  

 학위논문

 

0016934849

Date and Time of Latest Transaction  

20240214101702

ISBN  

9798380128377

DDC  

574

Author  

Karagiannis, Dimitrios.

Title/Author  

Epigenetic Targeting of Metabolic and Lineage Abnormality in Cancer - [electronic resource]

Publish Info  

[S.l.] : Columbia University., 2023

Publish Info  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Material Info  

1 online resource(139 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-02, Section: B.

General Note  

Advisor: Lu, Chao.

학위논문주기  

Thesis (Ph.D.)--Columbia University, 2023.

Restrictions on Access Note  

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

Abstracts/Etc  

요약Chromatin regulation is a major aspect of cancer development, progression, and treatment. Several small molecule inhibitors of chromatin regulators are currently used for treatment of certain hematological malignancies. However, there is still opportunity for many more patients to benefit from therapeutic approaches that target chromatin regulation, especially in the context of solid tumors. A critical unmet need is the identification of robust biomarkers that can guide the application of epigenetic inhibitors in a precise and personalized manner. In my dissertation, I aim to address this important knowledge gap by studying how perturbation of chromatin can target metabolic and lineage abnormalities in solid tumors for therapeutic benefit. To do this, I have focused on genetic and pharmacological perturbations of chromatin pathways in two cancer models: (1) lung adenocarcinoma (LUAD) with NRF2 activation and (2) neuroendocrine esophageal carcinoma (NEC).In the study on NRF2-active LUAD, we found that histone deacetylase (HDAC) inhibitors can be repurposed to reprogram the epigenomic and metabolic landscape, which leads to specific and potent anti-tumor effects in the context of NRF2 activation. Specifically, we employed a chromatin-focused genetic screen to identify dependencies on chromatin regulators. The screen revealed an NRF2-specific dependency on class I histone deacetylases. Experiments in mouse and human LUAD cell lines in vitro and in vivo indicated an NRF2-specific sensitivity to the class I HDAC inhibitor Romidepsin. Mechanistically, profiling of histone acetylation and gene expression upon Romidepsin treatment revealed a relative loss of histone H4 acetylation at promoters which was associated with reduced gene expression. Many downregulated genes were more essential for the survival of NRF2 hyperactive cancer cells, including genes involved in glutamine and serine metabolism, c-Myc and several of its targets involved in purine and pyrimidine synthesis. These transcriptional changes had corresponding effects on altering the metabolic pathways that NRF2-active cells selectively require for survival.In the study on neuroendocrine esophageal carcinoma (NEC), we identified a crucial role for epigenetic regulation of lineage fate through transcriptional control of the key epidermal transcription factor p63. This project originated from data from my collaborators that indicates a role for p63 in the suppression of basal-to-neuroendocrine identity transition in the developing esophagus. Consistently, I found that p63 is silenced in NEC through a non-genetic mechanism. Reintroducing p63 isoforms in a human NEC cell line showed that ΔNp63α was sufficient to restore squamous marker expression. An epigenetic drug screen assessing p63 gene expression and subsequent validation experiments revealed that inhibition of EZH2, a histone methyltransferase, induced expression of ΔNp63α and genes related to the squamous identity. Analysis of the chromatin state in the TP63 locus showed that EZH2 inhibition led to a loss histone H3 methylation and a gain of histone H3 acetylation and its reader BRD4. These results support the hypothesis that the squamous identity can be reactivated epigenetically in NEC through de-repression of ΔNp63α as a potential therapeutic strategy.Together, these studies contribute to our understanding of the transcriptional response to chromatin perturbation and show that this can be leveraged to modulate cell metabolism and identity, as well as to achieve therapeutic benefit in new contexts of cancer.

Subject Added Entry-Topical Term  

Biology.

Subject Added Entry-Topical Term  

Molecular biology.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Oncology.

Index Term-Uncontrolled  

Cancer

Index Term-Uncontrolled  

Cell fate

Index Term-Uncontrolled  

Epigenetics

Index Term-Uncontrolled  

Metabolism

Index Term-Uncontrolled  

Chromatin regulation

Index Term-Uncontrolled  

Neuroendocrine esophageal carcinoma

Index Term-Uncontrolled  

Lineage abnormality

Added Entry-Corporate Name  

Columbia University Genetics and Development

Host Item Entry  

Dissertations Abstracts International. 85-02B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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소장사항  

202402 2024

Control Number  

joongbu:643016