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Dissertation/Thesis Abstract

Identification of the JMJD3/KDM6B Interactome Reveals Novel Functions in Breast Cancer
by Sun, Yifei, Ph.D., Icahn School of Medicine at Mount Sinai, 2017, 183; 10634884
Abstract (Summary)

In this study, I show that JMJD3/KDM6B is overexpressed and corresponds with poor survival outcomes for many breast cancer patients. Loss of JMJD3/KDM6B leads to widespread defects in alternative RNA transcript splicing, whereby, several transcript alterations of critical regulatory gene products are evident. I also identify the JMJD3/KDM6B-centered interactome of proteins and RNAs bound by JMJD3/KDM6B. My studies reveal that JMJD3/KDM6B, participate along with its interacting protein partners such as deleted in breast cancer 1 (DBC1 or KIAA1967) and several other RNA binding proteins, to regulate the inclusion or exclusion of exons during transcriptional elongation with the DBC1/ZIRD (DBIRD) complex as a RNA polymerase II bound co-transcriptional splicing complex when bound to RNA transcripts. I confirm such interactions through my studies using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (or PAR-CLIP) to investigate RNA transcripts associated with JMJD3/KDM6B and DBC1. Of the many RNA transcripts bound by JMJD3/KDM6B and DBC1, I therefore identify critical transcripts known to regulate breast cancer cell growth, proliferation, and their potential for regulating tumor cell survival, migration and drug resistance.

Finally, I characterize the enzymatic function of JMJD3/KDM6B in breast cancer cell survival using the small molecule enzymatic inhibitor GSK-J4 of JMJD3/KDM6B (KDM6B) and UTX/KDM6A. Genomic data using this GSK-J4 inhibitor showed that demethylase activity of JMJD3/KDM6B (or UTX/KDM6A) influences mitochondria functionality in breast cancer. For functional analysis, I performed apoptosis, cell cycle, and mammosphere studies resembling stem cell activity, to show that enzymatic activity of JMJD3/KDM6B is required for forming mammospheres and maintaining cellular homeostasis of breast cancer cells.

Taken together, I have identified several novel interaction partners of JMJD3/KDM6B and mechanistically characterized the role of JMJD3/KDM6B in regulating alternative splicing and modulating cellular stability in mammary oncogenesis with its demethylase -dependent and -independent functionality.

Indexing (document details)
Advisor: Walsh, Martin J.
Commitee: Houten, Sander, Jian, Jin, Sharp, Andrew, Silva, Jose, Wang, Greg
School: Icahn School of Medicine at Mount Sinai
Department: Biomedical Sciences
School Location: United States -- New York
Source: DAI-B 79/02(E), Dissertation Abstracts International
Subjects: Biology, Genetics, Medicine
Keywords: Breast cancer, Epigenetics, Metabolism, Rna-binding, Splicing, Transcription
Publication Number: 10634884
ISBN: 978-0-355-43294-7
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