bims-meprid 2024-09-22 papers

Trends Cancer. 2024 Sep 13. pii: S2405-8033(24)00172-9. [Epub ahead of print]

Metabolism and epigenetics: drivers of tumor cell plasticity and treatment outcomes.

Benjamin N Gantner, Flavio R Palma, Madhura R Pandkar, Marcelo J Sakiyama, Daniel Arango, Gina M DeNicola, Ana P Gomes, Marcelo G Bonini.

Emerging evidence indicates that metabolism not only is a source of energy and biomaterials for cell division but also acts as a driver of cancer cell plasticity and treatment resistance. This is because metabolic changes lead to remodeling of chromatin and reprogramming of gene expression patterns, furthering tumor cell phenotypic transitions. Therefore, the crosstalk between metabolism and epigenetics seems to hold immense potential for the discovery of novel therapeutic targets for various aggressive tumors. Here, we highlight recent discoveries supporting the concept that the cooperation between metabolism and epigenetics enables cancer to overcome mounting treatment-induced pressures. We discuss how specific metabolites contribute to cancer cell resilience and provide perspective on how simultaneously targeting these key forces could produce synergistic therapeutic effects to improve treatment outcomes.

Keywords: cancer metabolism; epigenetics; histones; metabolites; novel therapeutics; post-translational modifications

DOI: https://doi.org/10.1016/j.trecan.2024.08.005

Nat Commun. 2024 Sep 18. 15(1): 8178

Nutritional vitamin B12 regulates RAS/MAPK-mediated cell fate decisions through one-carbon metabolism.

Ana Cristina Laranjeira, Simon Berger, Tea Kohlbrenner, Nadja R Greter, Alex Hajnal.

Vitamin B12 is an essential nutritional co-factor for the folate and methionine cycles, which together constitute one-carbon metabolism. Here, we show that dietary uptake of vitamin B12 modulates cell fate decisions controlled by the conserved RAS/MAPK signaling pathway in C. elegans. A bacterial diet rich in vitamin B12 increases vulval induction, germ cell apoptosis and oocyte differentiation. These effects are mediated by different one-carbon metabolites in a tissue-specific manner. Vitamin B12 enhances via the choline/phosphatidylcholine metabolism vulval induction by down-regulating fat biosynthesis genes and increasing H3K4 tri-methylation, which results in increased expression of RAS/MAPK target genes. Furthermore, the nucleoside metabolism and H3K4 tri-methylation positively regulate germ cell apoptosis and oocyte production. Using mammalian cells carrying different activated KRAS and BRAF alleles, we show that the effects of methionine on RAS/MAPK-regulated phenotype are conserved in mammals. Our findings suggest that the vitamin B12-dependent one-carbon metabolism is a limiting factor for diverse RAS/MAPK-induced cellular responses.

DOI: https://doi.org/10.1038/s41467-024-52556-3

Neoplasma. 2024 Aug;pii: 240127N41. [Epub ahead of print]71(4): 319-332

High histone H3K18 lactylation level is correlated with poor prognosis in epithelial ovarian cancer.

Jinyu Chao, Guan-di Chen, Shu-Ting Huang, Haifeng Gu, Yue-Yang Liu, Yiheng Luo, Zidan Lin, Zhi-Zai Chen, Xiaoli Li, Bin Zhang, Xifeng Xu, Shanyang He.

Protein lactylation has a poor prognosis in malignant tumors, but its impact on the prognosis of epithelial ovarian cancer (EOC) remains unknown. We analyzed 112 patients with EOC. Immunohistochemical staining was used to detect the level of pan lactylation (Pan Kla) and histone H3K18 lactylation (H3K18la) in the EOC tissues and normal ovarian tissues. The result showed that the protein lactylation level in EOC was higher than in normal tissues. Then, we analyzed the relationship between overall survival (OS), progression-free survival (PFS) of EOC, and lactylation. The result showed that patients with high histone H3K18la levels had poorer OS (p=0.028) and PFS (p<0.001). Multivariate Cox regression analysis of PFS showed histone H3K18la was an independent risk factor (p=0.001). In addition, we found that both histone H3K18la and Pan Kla in the cytoplasm were associated with platinum recurrence time (p=0.002/p=0.003). The results also indicated that the H3K18la level was related to a tumor stage (p=0.037). Furthermore, we explored the effects of lactylation on the metastasis of ovarian cancer. The results indicated a significant increase in migration in the promoter group compared to the negative control group and inhibitor group. In conclusion, high histone H3K18la level is associated with poor prognosis in EOC. Protein lactylation may have a significant impact on EOC and could potentially be used as a target for EOC therapy in the future.

DOI: https://doi.org/10.4149/neo_2024_240127N41