Written by Charlotte Harrison, Science Writer.
A study published in PNAS has identified a new role for the metabolite succinate in breast cancer metastasis. The study also showed that the enzyme PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) regulates succinate levels during breast cancer progression.
As such, PLOD2 could be a promising target in metastatic breast cancer.
Changes in succinate
Succinate levels are altered in many types of cancer. To find out how succinate regulates cancer progression, the authors used isotope-resolved metabolomic analysis to measure metabolite levels during the epithelial-to-mesenchymal transition (EMT) – the process that mobilises cancer cells.
They detected changes in the levels of hundreds of metabolites in mammary epithelial cells, including increased cytoplasmic succinate levels.
Then, when cells were treated with succinate, they developed a mesenchymal phenotype, and had enhanced cancer-cell stemness and increased colonization potential. Chromatin immunoprecipitation and sequence analysis showed that increased succinate levels led to reduced accumulation of the transcriptional marker 5hmC and transcriptionally repressed EMT-related genes.
“The results reveal a previously unidentified function of succinate and its role in breast cancer metastasis, filling a critical gap in our knowledge regarding how changes in metabolites promote cancer cell plasticity,” said author Ren Xu in a press release.
Changes in PLOD2
To determine how succinate is regulated during EMT, the authors next analysed changes in gene expression. The mRNA levels of several metabolic dioxygenases were induced during the EMT of mammary epithelial cells, of which PLOD2 had the highest expression.
Further studies confirmed that PLOD2 expression was increased during the EMT process, and that this increased PLOD2 expression caused cytoplasmic succinate levels to increase.
When PLOD2 expression was silenced in mammary epithelial cells, levels of succinate decreased, the mesenchymal phenotype and stemness were abolished, and 5hmC levels increased. Then, when PLOD2-silenced cells were treated with succinate, cancer-cell stemness returned. These results indicate that PLOD2 promotes cancer progression at least in part by altering succinate levels.
Together, the results indicate that targeting PLOD2 might be a way to suppress breast cancer metastasis. “As PLOD2 is a druggable target, these findings could pave the way for the development of new therapies to stop cancer progression,” said Xu.