Deciphering the role of transcription factors in glioblastoma cancer stem cells

Abstract

Glioblastoma (GBM), the most aggressive and fatal brain malignancy, is largely driven by a subset of tumor cells known as cancer stem cells (CSCs). CSCs possess stem cell-like properties, including self-renewal, proliferation, and differentiation, making them pivotal for tumor initiation, invasion, metastasis, and overall tumor progression. The regulation of CSCs is primarily controlled by transcription factors (TFs) which regulate the expressions of genes involved in maintaining stemness and directing differentiation. This review aims to provide a comprehensive overview of the role of TFs in regulating CSCs in GBM. The discussion encompasses the definitions of CSCs and TFs, the significance of glioma stem cells (GSCs) in GBM, and how TFs regulate GSC self-renewal, proliferation, differentiation, and transformation. The potential for developing TF-targeted GSC therapies is also explored, along with future research directions. By understanding the regulation of GSCs by TFs, we may uncover novel diagnostic and therapeutic strategies against this devastating disease of GBM.

1. Introduction

Glioblastoma (GBM) is one of the most common and highly invasive types of heterogeneous glioma tumors encountered clinically. The 5-year survival rate is very low, reflecting a high recurrence rate of more than 90% for GBM, and despite adjuvant therapy with temozolomide (TMZ) chemotherapy and radiotherapy (RT), the prognosis remains poor [1]. Tumor recurrence is closely related to stem cell-like characteristics in the tumor region [2]. Cancer stem cells (CSCs), an abnormal and uncontrolled subgroup of tumor cells known for their self-renewal and multilineage differentiation abilities, contribute to the formation of various tumor cell types [3]. Gliomas have two cell types: glioma stem cells (GSCs) and differentiated tumor cells [4]. Notably, some commonalities can be observed in GSCs within GBM, such as self-renewal, nondifferentiation, tumor invasion, and drug resistance, as well as differences in marker expression and differentiation potential [5]. These intrinsic limitations of GSCs have become obstacles in the field of GBM treatment.

In the human genome, there are at least 1600 transcription factors (TFs), approximately 19% of which are related to disease phenotypes [6]. TFs regulate nearly the entire genome through one domain that binds to a specific DNA sequence and another that binds to protein coactivators or corepressors [6,7]. The phenotypic characteristics of GBM are mediated by a series of signaling pathways and mutations, and TFs are instrumental in controlling genes that govern GSC maintenance, differentiation, and tumorigenicity. TFs adjust gene expression in response to various intracellular and extracellular environments (hypoxia) and signals [epithelial–mesenchymal transition (EMT), cell cycle, apoptosis, metabolic reprogramming]. Importantly, they facilitate the interactions of CSCs with their surrounding microenvironment, including their stemness, matrix, and immune system [8]. Furthermore, highly specific TFs usually only regulate a limited set of gene targets; hence, inhibitors of such TFs are less likely to affect compensatory drug resistance mechanisms common to many drugs. Currently, strategies for effectively treating diseases by targeting abnormal TFs, which involve disrupting multiple attributes of tumor cells through the blockade of TFs, ultimately leading to tumor regression, have been proposed. Unsurprisingly, considerable effort and resources have been invested in identifying small molecules that can effectively and specifically inhibit TFs. Therefore, inhibitors related to TFs in GBM have a wide range of clinical applications (Table 1).