New findings, published in Molecular Cell, illustrate how tumors manage to feed and grow despite their relentless surroundings.
An enzyme known as acetyl-CoA synthetase 2 (ACSS2) is at the center of providing tumors with a route to survive. ACSS2 enhances the tumor’s ability to use acetate, a cellular salt, as a carbon-based source of food, instead of glucose. While glucose is more desirable to aid tumor growth, its supply in cancer cells is often limited.
Acetate provides the cancer cells that are located at the core of the tumor with a lifeline to not only survive while struggling with nutrient deficiency, but also a method to grow.
Cutting off this important nutrient pathway in cancer cells could be essential to preventing tumor growth and promoting cancer cell death. However, the immune system is unable to stop the nutrient pathway in cancer cells, and current therapies are ineffective.
Furthermore, it is not clear how ACSS2 travels from a liquid cell component called cytosol into the nucleus in a process known as nuclear translocation. If the nuclear translocation of ACSS2 could be stopped, so too would the cancer cell’s ability to maintain itself.
“Overcoming metabolic stress is a critical step in solid tumor growth. Acetyl coenzyme A (CoA), generated via glucose and acetate uptake, is a key carbon source for important cellular processes such as histone acetylation and gene expression,” says Zhimin Lu, Ph.D., professor of neuro-oncology and lead researcher of the study.
“However, how acetyl CoA is produced under nutritional stress is unclear. Our study explains the underlying mechanics of how this occurs, with ACSS2 as a novel and important method for gene expression under these circumstances.”
ACSS2 allows production of cellular structures to aid tumor development
Lu and colleagues used a gene-editing tool called CRISPR to explore the role of ACSS2 in histone acetylation by generating nuclear acetyl CoA from acetate inside the nucleus of the cell.
Histones are vital for gene regulation. They are proteins that act as “spools” for DNA to wind around. Histone acetylation is a modification process that is a key part of gene expression. Histone modification using a metabolic enzyme was found to be significant for cells to remain stable and for the development of tumors.
The ACSS2 enzyme allows lysosomes, which are cellular structures that are known to contribute to tumor development, to be produced. Moreover, ACSS2 promotes autophagy – a “cannibalistic cell-feeding mechanism” – which, in turn, enables lysosomes to obtain, digest, and recycle key nutrients.
What is more, if nutrients outside the cell are in short supply, ACSS2 reprograms the cancer cell’s metabolism for cell survival and growth in two ways: by increasing autophagy, and by reusing products digested by lysosomes.
“These findings elucidate an instrumental interplay between reprogramming of metabolism and gene expression in cancer cells.
Inhibition of both ACSS2’s nuclear function and the metabolic pathway, known as glycolysis, which converts glucose to tumor-feeding energy, appears to be an efficient approach for cancer treatment.”
Zhimin Lu, Ph.D.
The research provides new information regarding nuclear translocation and how ACSS2 could be a potential player in new therapeutic approaches for treating cancer.