2023-05-15 11:45:06
The search for the origin of a rare tumor points to a little-studied mechanism as a new focus of interest in cancer research: “succinylation”.
Researchers from the National Cancer Research Center (CNIO) in Spain have discovered that one of the causes of the development of the rare tumors pheochromocytoma and paraganglioma is the interruption of a very specific step in the manufacture of some proteins, called succinylation. This is a relatively little-studied mechanism that could be involved in more diseases than previously thought, judging by the results of the new study.
The researchers find that defects in the DLST protein prevent succinylation, and therefore DLST is a promising therapeutic target to treat diseases linked to dysregulated succinylation.
A mutation that causes pheochromocytoma and paraganglioma tumors
Proteins are the building blocks of the body, the structural component of tissues and organs. They are also the nanomachines that carry out all biological functions. There are tens of thousands of different human proteins, and each one has its tasks: transporting oxygen in the blood, contracting muscles, reading DNA… even making other proteins. The appearance of a cancer always implies that there are proteins that do not work well.
Alberto Cascón and Sara Mellid, from the CNIO Hereditary Endocrine Cancer Group, wanted to understand what was failing in five specific patients with pheochromocytoma and paraganglioma. The incidence of these rare tumors, really considered a single disease, is three to eight cases per million inhabitants each year.
Over the last decade, this CNIO group has discovered 5 of the 22 genes implicated in the disease identified so far.
In the case of the five patients whose analysis has led to the new result, the researchers knew the causative mutation, because they discovered it themselves in 2019. But they did not know what was going wrong in the cells due to that mutation.
Alberto Cascón and Sara Mellid, researchers from the Hereditary Endocrine Cancer Group of the CNIO (Centro Nacional de Investigaciones Oncológica), at the entrance of the centre. (Photo: Laura M. Lombardía / CNIO)
Failures in cell metabolism, pseudohypoxia and cancer
Proteins are made according to instructions written in genes; mutations equal wrong instructions. The mutations studied by Cascón and Mellid affect the DLST protein, involved in cell metabolism. It is known that when there are failures in some proteins related to cell metabolism, pseudohypoxia can occur, a situation in which tumor cells increase glycolysis as a way to obtain energy, even in the presence of oxygen, which is an advantage for them.
The CNIO researchers discovered that the mutated DLST protein effectively generates this pseudohypoxia that favors cancer, by preventing other proteins from being manufactured correctly. Specifically, it prevents other proteins from being succinylated.
Succinylation is one of the last steps in the manufacture of some proteins. Genetic information dictates which pieces make up the protein and in what order they should be arranged; but after the pieces are assembled, like beads on a necklace, they often need to be further completed with specific molecules, which are attached as clasps to the necklace. These “ornaments” change the function of proteins.
In succinylation, the succinyl chemical group is added to the protein. It is a mechanism that has not yet been studied, “but it seems to be very important for the function of proteins and it is beginning to be widely studied not only in cancer, but also in other diseases,” Cascón and Mellid point out.
“We see that when the DLST protein has the mutations that we have found in patients with PPGL, succinylation does not occur, and this causes many key proteins for cell function to be hyposuccinylated,” they explain.
“The fact that the proteins are not succinylated correctly is what we propose as one of the mechanisms that could give rise to the tumor. The hyposuccinylated proteins in pheochromocytoma and paraganglioma are involved in several processes, and when they do not function correctly, they end up triggering pseudohypoxia that favors the tumor cells”, point out Sara Mellid and Alberto Cascón.
The study is titled “DLST mutations in pheochromocytoma and paraganglioma cause proteome hyposuccinylation and metabolic remodeling”. And it has been published in the academic journal Cancer Communications. (Source: CNIO)
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