Background: Exploring susceptibility to cuproptosis in colorectal cancer

A study published in PNAS reports that lactylation of the NAT10 protein in colorectal cancer is linked to RNA modification and promotes cuproptosis, a form of copper-dependent cell death. The researchers identified modification of NAT10 at lysine 426 (K426) and the opposing regulatory role of SIRT1. They also reported results from combining a cuproptosis inducer with a SIRT1 inhibitor, but the available abstract is insufficient to assess therapeutic benefit in patients.

Cuproptosis is being studied as an anticancer strategy, but its clinical application remains limited. In this study, copper levels and expression of DLAT, which contributes to promoting cuproptosis, were elevated in colorectal cancer tissue. The researchers interpreted these increases as clues that colorectal cancer may be susceptible to cuproptosis. These observations alone cannot explain the cause of copper accumulation or patients’ treatment responses.

Key findings: K426 lactylation and opposing regulation by SIRT1

The study focused on NAT10, an RNA-modifying enzyme. NAT10 mediated N4-acetylcytidine (ac4C) modification of DLAT messenger RNA (mRNA), increasing mRNA stability and promoting cuproptosis. This links chemical modification of RNA to the regulation of cell death.

Lactylation at NAT10 K426 increased NAT10’s catalytic activity. In contrast, SIRT1 mediated removal of lactylation, or delactylation, at this site, leading to suppression of cuproptosis. The findings indicate that the modification state of a specific site should also be considered when assessing NAT10 function.

The researchers reported inducing cuproptosis in colorectal cancer by combining the cuproptosis inducer elesclomol with the SIRT1 inhibitor selisistat. However, the abstract does not specify the experimental model configurations, treatment doses, or effect sizes compared with treatment using either agent alone. The results therefore cannot be interpreted as demonstrating synergy or clinical efficacy.

The feedback process requires distinguishing a decrease in soluble DLAT from DLAT supplementation. A decrease in soluble DLAT following elesclomol treatment increased NAT10 K426 lactylation. The researchers also reported that DLAT supplementation formed a positive feedback loop that amplified cuproptosis. However, the detailed steps connecting these events and the specific method used for the supplementation experiments cannot be confirmed from the provided abstract alone.

Implications and outlook: A candidate therapeutic pathway and questions for validation

This study connects a protein modification of NAT10, ac4C modification of DLAT mRNA, and cuproptosis. The opposing regulation by SIRT1 and the drug combination results provide further grounds for investigating this pathway as a target in subsequent cancer research.

The available material is limited to bibliographic information and the abstract. Sample sizes, effect sizes, treatment duration, and toxicity in normal tissues cannot be determined, and the material includes no clinical results supporting improved patient survival or tumor response. The researchers present the therapeutic potential of targeting this pathway. Developing it into an actual treatment strategy will require validation of reproducibility across models, safety, and therapeutic efficacy.

The study is described in the paper abstract indexed by Europe PMC.