Kattan, Shahad
(2017)
The regulation of chromatin and transmission of epigenetic information by the heterochromatin protein 1, binding protein 3 (HP1BP3) in normal and colorectal cancer cells.
PhD thesis, University of Nottingham.
Abstract
The heterochromatin-associated proteins are subject to several different posttranslational modifications; hence, their level must be tightly controlled; otherwise as transcription factor co-repressor(s) complexes with these proteins, it may lead to stable silencing. An obvious mechanism to limit the expression time of a protein is to destroy it via the ubiquitin-proteasome system. FBXW7 (F-box and WD repeat domain–containing 7) is an E3-ligase targets transcriptional modulators and proto-oncogenes for degradation with crucial functions in cell-fate determination and tumorigenesis. In addition, most of current studies focused on epigenetic modifications that influence on the core histones within the euchromatin-heterochromatin transition, whereas the heterochromatin proteins and their partners’ identity remained largely unclear.
Dr Nateri’s lab have recently identified several proteins which are targeted by the FBXW7 E3 ligase for the ubiquitin-mediated degradation. Among others, my study was focused on the role(s) of heterochromatin protein– binding protein 3 (HP1BP3) protein in epigenetic-reprogramming and its underlining mechanisms, including EMT and cell cycle progression, in normal and cancer cells. It's worth mentioning that apart from the single publication (Hayashihara et al., 2010a), the role of HP1BP3 was unknown when I began my project.
HP1BP3 modulates the entry/exit of nucleosomal-DNA through binding to HP1α protein. HP1α is enriched in the pericentromeric heterochromatin, and it has been reported that HP1α recruitment in this region depends on SUV39H1/2-mediated H3K9 trimethylation.
Widespread epigenomic alterations, occurs during cell differentiation, cell cycle progression and malignant transformation, but how epigenetic mechanisms contribute to the transcriptional reprogramming that accompanies EMT is still poorly understood. Furthermore, chromatin modulation events are important to control the cell-cycle-dependant gene expression during development and differentiation. Dysregulated expression of upstream cell-cycle regulators can affect DNA replication, repair, and/or division, leading to carcinogenic.
Herein, our data show that the loss of FBXW7 mediated HP1BP3 induction alters heterochromatin states, through rescuing HP1α from its repressive function, impairing SUV39H1-mediated the methylation of histone H3 lysine 9 (H3K9me3), and stimulating the acetylation of H3K9 (H3K9ac) that lead to activation of epithelial-mesenchymal transition (EMT) pathway in Tiger skin fibroblast and HCT116 human colorectal cell lines. This induction of HP1BP3 upregulates the level of mesenchymal markers/regulators (Ncadherin, ZEB-1, Vimentin, and Snail1) in Tiger fibroblast cells while downregulating the epithelial marker (E-cadherin) and upregulating mesenchymal markers (ZEB-1, Vimentin, and Snail1) in HCT116 cells. In addition, upregulated HP1BP3 is an inducer of both G2/M cell cycle arrest and G1 to S phase transition via downregulating Cyclin B1 and SUV39H1/H3K9me3 while upregulating H3K9ac mark, in human Tiger fibroblasts and HCT116 CRC cells.
Taken together, these findings point towards the important biological functions of HP1BP3 and its contribution in regulation of chromatin/EMT associated genes expression which consequently can be implicated in the pathogenesis of different types of FBXW7-mutated cancer.
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