The Tumor Suppressive Functions of Histone Methyltransferase SETD2 in Lung Adenocarcinoma Amy Claire Gladstein

Format:

Book

Thesis/Dissertation

Author/Creator:

Gladstein, Amy Claire, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

0307.

0369.

0379.

0982.

0992.

Local Subjects:

0307.

0369.

0379.

0982.

0992.

Physical Description:

1 electronic resource (157 pages)

Contained In:

Dissertations Abstracts International 87-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Lung cancer is the leading cause of cancer-related deaths in the United States and is characterized by a high mutational burden and limited therapeutic options. While recent efforts have focused on the generation of targeted therapies, little is known about how chromatin modifiers influence tumor initiation and development, even though the genes encoding these enzymes are frequently altered in lung adenocarcinoma. The histone 3 lysine 36 (H3K36) trimethyltransferase SETD2 is mutated in ~7% of lung adenocarcinoma patients, but the mechanisms by which SETD2 regulates tumor growth are poorly understood. To address this gap in knowledge, we used KRAS-driven mouse models of lung adenocarcinoma to model Setd2 inactivation. First, we identified metabolic pathway alterations as targetable features of Setd2 inactivation. Specifically, we found that SETD2-deficient tumors have upregulated mitochondrial metabolism, protein translation, and mTORC1 signaling, and that these pathways confer therapeutic vulnerabilities to SETD2-mutant tumors. Further, using the H3K36M oncohistone as a tool to model H3K36 methyltransferase inhibition, we uncovered a complex mechanism by which H3K36 methylation state drives immune surveillance or immune evasion. Expression of H3K36M or inactivation of the major H3K36 dimethyltransferase, Nsd2, promoted the derepression of endogenous retroviral elements, leading to the formation of dsRNA, and activation of a potent anti-tumor immune response. However, additional inactivation of the H3K36 trimethyltransferase, Setd2, opposed dsRNA formation and restored tumor growth. Together, these studies broaden our understanding of the function of H3K36 methyltransferases in cancer and suggest actionable therapeutic strategies for targeting metabolic and immunologic weaknesses in lung adenocarcinoma

Notes:

Advisors: Feldser, David M. Committee members: Simon, M. Celeste; Wellen, Kathryn E.; Asangani, Irfan A.; Capell, Brian C.

Source: Dissertations Abstracts International, Volume: 87-07, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276006512

Access Restriction:

Restricted for use by site license