Investigating the role of HP1BP3 heterochromatin protein in colorectal cancer cells and intestinal organoids under normoxic and hypoxic conditions
Publication Date
March 15, 2026
Creator
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths. Alarmingly, recent studies reported that there is an increasing incidence of CRC among younger adults (under 50 years old) in several high- and mid-income countries, including the UK. Researchers have identified mutations in certain genes that is associated with cancer and can transform normal cells into cancerous cells. In addition, problems with how our genetic material is organised and controlled, known as epigenetic changes, can disrupt tissue homeostasis and play a major role in cancer growth and progression. However, the role of certain heterochromatin-associated proteins that are linked to tightly packed genetic material, and their contribution in keeping tissues healthy and in cancer development, remains poorly understood.
Heterochromatin protein 1 binding protein 3 (HP1BP3) is a nucleoprotein associated with heterochromatin and was first identified as a binding partner of heterochromatin protein 1α (HP1α). It may affect the chromatin state by controlling how nucleosomal DNA enters and exits. HP1BP3 might also promote heterochromatin formation during hypoxia (low-oxygen conditions). HP1α is known as a transcriptional repressor because it interacts with SUV39H1, an H3K9 methyltransferase involved in heterochromatin formation, and acts as an epigenetic silencer of genes. It appears that the binding of HP1BP3 to HP1α overlaps, in terms of amino acid sequences, with the site where SUV39H1 interacts with HP1α. Therefore, it is postulated that an overexpression of HP1BP3 in colorectal cancer may promote growth and gene expression activation, through a possible competition with SUV39H1 for binding to HP1α. However, despite what is known, the mechanism and biological activity of HP1BP3 in colorectal cancer remain poor.
This study aimed to elucidate the role of HP1BP3 as an epigenetic modulator in colorectal cancer cells under both normoxic and hypoxic conditions. The way HP1BP3 contributes to epigenetic mechanisms in CRC is still not fully understood. Specifically, it is examined the effects of HP1BP3 loss in DLD-1 (DLD-1HP1BP3-/-) and HCT116 (HCT116HP1BP3-/-) colorectal cancer cell lines and murine intestinal organoids (Hp1bp3∆G).
The findings suggest that HP1BP3 plays an important role in responding to hypoxia, possibly by modulating HIF-1α and its downstream genes in these cell lines. With the observation that overexpression of HP1BP3 is linked to lower levels of H3K9me3 and higher levels of H3K9ac, while knockout of HP1BP3 leads to the opposite: increased H3K9me3 and reduced H3K9ac levels. These data are presented in Chapter 3.
Further, we found that HP1BP3 knockout significantly slows cell growth and colony formation by causing more cells to stop at the G1 phase of the cell cycle. It also affects cell shape and reduces the ability of cells to close a wound gap. In addition, a lack of HP1BP3 reduces EMT activity, leading to fewer colonospheres and less symmetrical division of stem cells. These results are presented in Chapter 4.
Organoids were generated from mouse intestinal crypts in which Hp1bp3 had been conditionally deleted (Hp1bp3∆G) in the intestine and compared with organoids from wild-type floxed mice (Hp1bp3fl/fl). The Hp1bp3∆G organoids showed slower budding and branching, with a marked decrease in markers of stemness and cell proliferation. These findings are discussed in Chapter 5.
In summary, this study helps to clarify the role of HP1BP3 in CRC cells, showing that it acts as a scaffold protein that may reprogram chromatin structure and, in doing so, modulate gene expression. These processes play critical roles in maintaining tissue homeostasis and driving cancer progression. With additional research, as indicated in the last chapter, this insight could assist new strategies that lead to the creation of new cancer treatment options.
Item Type
ethesis
Thesis Type
PhD
Supervisors
McIntyre, Alan
Subjects (LC)
Associated Schools / Departments
School of Medicine
eprints ID
83033
UoN Repository URI
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