The Role of ZFHX4 in Regulating the Cancer Stem Cell State

Illustrated by Angela Chen

Gliomas are a class of primary brain tumors that originate from glial cells, which are cells that support the function of neurons in the central nervous system. This class of tumors includes astrocytic tumors, oligodendrogliomas, ependymomas and mixed gliomas. Within the group of primary astrocytomas, glioblastoma multiforme is the most malignant and commonly occurring astrocytoma, a type of brain tumor that originates from astrocytes. Glioblastoma (GBM) is a devastating disease that accounts for more than 60% of adult primary brain tumors. A number of unique genetic alterations have been identified to be commonly associated with primary GBM. These alterations include epidermal growth factor receptor (EGFR) gene mutation and amplification, overexpression of mouse double minute 2 (MDM2), deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A) and loss of heterozygosity (LOH) of chromosome 10q, which contains the phosphatase and tensin homolog (PTEN) gene and telomerase reverse transcriptase (TERT) promoter mutation [1].  Despite an aggressive standard of care, five-year survival remains under 5%. Since GBM is one of the most prevalent and difficult to treat gliomas, it has been at the forefront of brain tumor research. 

Much of the difficulty in treating GBM may be due to tumor-initiating cells (TICs), which are stem-like, multipotent cells that are more resistant to radiation than the rest of the tumor [2]. Multipotent cells are special as they can differentiate into multiple different cell types. These stem cells exhibit two properties that complicate treatment of GBM stem cells: self-renewal and maintenance of tumor heterogeneity. Self-renewal is the property of stem cells to produce at least one daughter cell that maintains the stem-like properties. This process occurs in addition to the differentiation of the stem cell, enabling a single stem cell to replicate into a stem cell and a differentiated cell. In a tumor, this enables stem cells to proliferate while maintaining the initial stem cell population [2]. This is problematic as stem cells tend to be resistant to traditional forms of tumor therapy, so tumor recurrence is commonplace in cancer stem cells and leads to poorer patient prognosis. 

There are a wide variety of mechanisms that create stemness in GBM TICs, including kinases, phosphatases, Bmi1 oncogene proteins and transcription factors and chromatin binding factors [4]. Zinc finger homeobox protein 4 (ZFHX4) is a transcription factor required for the GBM stem cell state, and has demonstrated that it interacts with chromodomain-helicase-DNA-binding protein 4 (CHD4), a subunit of the Nucleosome Remodeling and Deacetylase (NuRD) complex. A useful procedure to analyze protein interactions is chromatin immunoprecipitation followed by mass DNA sequencing (ChIP-Seq). This procedure involves determining a genomic region of interest, allowing DNA-binding proteins to bind along fragments of the DNA region, and then visualizing the binding of proteins along the genome with selective antibodies and sequencing. ChIP-Seq data has shown that ZFHX4 and CHD4 colocalize throughout the genome of GBM stem cells to regulate expression of known oncogenic drivers and stem cell factors. Additionally, transcriptomic data collected from both in vitro GBM stem cell models and patient tumor samples have demonstrated a strong correlation between ZFHX4 expression and expression of stem cell associated genes including EGFR, NES, SOX2, and MYC [4]. Collectively, these data define the ZFHX4-CHD4 interaction as a promising target for novel therapies to disrupt the GBM stem cell state.

Epigenetic regulatory mechanisms have entered the forefront of cancer research, and the role of ZFHX4 in GBM stem cell treatment is a prime example of that. Traditional forms of cancer therapy are not only coupled with many negative side effects, but are also resisted by cancer stem cells [3]. By identifying the specific mechanisms by which cancer stem cells are maintained, new treatment options can be designed to target these mechanisms. New cancer treatments can target the mechanisms by which ZFHX4 interacts with CHD4 to disrupt the cancer stem cell state, thereby improving GBM patient outcomes with lesser drug toxicity. 

Edited by: Akshay Govindan
Illustrated by: Angela Chen

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