A transcription factor has been identified to be the main factor responsible for the tendency of glioblastoma stem cells to form tumours.
A group of researchers, guided by Professor Fang Zhiyou and Professor Chen Xueran from the Hefei Institutes of Physical Science (HFIPS), have discovered that Oct4A is the determinant transcriptional factor that gives rise to the glioblastoma stem cells’ (GSCs) tendency to form tumours.
Palmitoylation – a process in which fatty acids like palmitic acid are attached to cysteine, serine, and threonine residues of proteins – of Oct4A, catalysed by ZDHHC17 (palmitoyltransferase), is essential for Oct4A’s resistance to lysosomal degradation. This contributes to the malignancy of glioblastoma multiforme (GBM), which is one of the deadliest human cancers with one of the lowest median survival times of about a year.
GBM is the most widely seen primary intracranial tumour in adults and is the most harmful due to its high malignancy, uncontrollable growth, and ability to spread to other parts of the body. Glioblastoma stem cells (GSCs) are also suspected to be responsible for the resistance of glioblastomas to anticancer therapies such as chemotherapy and radiotherapy. Thus, a better understanding of the mechanisms that contribute to the malignancy of GSCs would aid in developing more effective therapies for this deadly cancer.
Octamer-binding transcription factor 4 (Oct4) belongs to a group of POU — a family of proteins that have well-conserved homeodomains — transcription factors. It is the main transcription factor responsible for the pluripotency of stem cells. Its various transcription start sites encode several mRNA isoforms that are involved in the regulation of development. However, the exact mechanism and biological function of the translated proteins have not been discovered.
The researchers discovered that out of the three Oct4 variants, Oct4A is key in causing GSCs to retain their tumorigenic activity. Furthermore, they also discovered that Sox4 and Oct4A formed interactions with each other at the SOX2 enhancer region, which allowed the glioblastoma stem cells to preserve their stemness – their ability to form differentiated cells and maintaining their self-renewal functions by keeping the processes of proliferation, quiescence, and regeneration in balance. DNA hypomethylation, which also upregulates the expression of the OCT4 gene, is likely to be the key culprit of the upregulation of stemness gene expression in recurrent gliomas.
To verify if Oct4A palmitoylation would be a potential therapeutic target for the treatment of gliomas, the researchers tested the effects of competitive inhibitors that interfered with Oct4A palmitoylation and found that it reduced the stemness and the tumorigenic activity of the GSCs.
“These findings indicate that Oct4A plays a role in the tumorigenic activity of glioblastoma,” said Chen Xueran, who conducted the research, “while Oct4A palmitoylation may be a candidate therapeutic target.”
Source: Chen et al. (2022). Oct4A palmitoylation modulates tumorigenicity and stemness in human glioblastoma cells. Neuro-Oncology.