Inhibition of HDAC7 Using RNAi As an Epigenetic- Based Therapy in Targeting Malignancies

Hassan, Ola

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Year:: 2024
Contributor:: Hassan, Ola (creator); Tapinos, Nikos (Advisor); Bertone, Paul (Reader); El-Deiry, Wafik (Reader); Sanders, Jennifer (Reader); Fiser, Andras (Reader); Brown University. Biology and Medicine: Pathobiology (sponsor)
Genre:: theses
Subject:: Cancer; epigenetics; Cancer--Treatment; Drugs--Design
Extent:: , None p.

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Abstract:: Abstract of Inhibition of HDAC7 Using RNAi As an Epigenetic- Based Therapy in Targeting Malignancies, by Ola Hassan, Ph.D., Brown University, May 2024. Class IIa histone deacetylases (HDACs) are a family of enzymes that, despite their name, do not have any measurable histone deacetylase activity, but they function as multi-protein interaction hubs due to the presence of a prolonged N-terminal domain. This dissertation identifies HDAC7, a member of the Class IIa HDAC family, as a critical epigenetic regulator in cancer pathogenesis and a potential therapeutic target. High HDAC7 expression correlates with poor local and global cancer patient survival, highlighting its importance. We employed a range of cultural assays, genome-wide omics, and proteomics techniques to comprehensively investigate the mechanistic implications of targeting HDAC7 in cancer. Phenotypic and transcriptomic analyses after inhibiting HDAC7 reveals significant alterations in cancer phenotype and gene expression in cancer stem cells (CSCs), suggesting its role in tumor progression and cancer patients’ survival. HDAC7 drives the stemness of CSCs to embryonic phenotype and enriches cell cycle and tumorigenic activities, whereas, inhibiting HDAC7 induces stemness phenotype change in CCSs. Utilizing a rigorous drug design pipeline, we developed a therapy specifically targeting HDAC7. Additionally, we demonstrate that HDAC7, a member of the Class IIa HDAC family, is a chaperone for Histone H3.3 and interacts with H3.3 and HIRA on chromatin. Specific inhibition of HDAC7 expression with subtype-specific siRNAs results in inhibition of the interaction of H3.3 with HIRA, while the association of H3.3 with DAXX and H3K9me3 is significantly increased, resulting in H3.3 being deposited on H3K9me3+/DAPI+ heterochromatin nuclear foci. Inhibition of HDAC7 triggers a significant increase of heterochromatin marks H3K9me3 and H3K27me3, global heterochromatin spreading in cancer cells, and reprogramming of the H3.3 chromatin landscape. This drives substantial alteration of cancer cell gene expression as well as inhibition of the stemness phenotype for cancer cells. Our work demonstrates the involvement of HDAC7 in the euchromatic H3.3 chaperone network and shows that inhibiting HDAC7 induces H3.3 landscape reprogramming, heterochromatin spreading, and epigenetic restriction in cancer cells.
Notes:: Thesis (Ph. D.)--Brown University, 2024

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Citation

Hassan, Ola, "Inhibition of HDAC7 Using RNAi As an Epigenetic- Based Therapy in Targeting Malignancies" (2024). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:xy9gs9ry/

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Pathobiology Theses and Dissertations

Theses and Dissertations for the Pathobiology department.
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