NNMT-DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition

Advanced Science, 2023 · DOI: 10.1002/advs.202202642 · Published: November 16, 2022

Simple Explanation

This study identifies that cancer cells sensitive to OXPHOS inhibition have increased OXPHOS activity and silenced nicotinamide N-methyltransferase (NNMT) expression. The expression of NNMT negatively correlates with OXPHOS inhibition sensitivity, downregulating intracellular S-adenosyl methionine (SAM) levels. DNA methyltransferase 1 (DNMT1) expression positively correlates with OXPHOS inhibition sensitivity, forming the NNMT-DNMT1 axis that determines cancer cell reliance on mitochondrial OXPHOS.

Study Duration

Not specified

Participants

62 tumor samples from a clinical trial

Evidence Level

Not specified

Key Findings

1
OXPHOS inhibition-sensitive cancer cells exhibit increased OXPHOS activity and silenced NNMT expression.
2
NNMT expression is negatively correlated with OXPHOS inhibition sensitivity, while DNMT1 expression shows a positive correlation.
3
Treatments using OXPHOS inhibitors hamper the growth of mouse tumor xenografts derived from OXPHOS inhibition-sensitive cancer cells but not resistant ones.

Research Summary

This study identifies cancer cell lines that are sensitive or resistant to OXPHOS inhibition and reveals that the NNMT-DNMT1 axis plays a critical role in determining cancer cell reliance on mitochondrial OXPHOS. The study demonstrates that NNMT expression negatively correlates with OXPHOS inhibition sensitivity, while DNMT1 expression positively correlates. The retrospective study of tumor samples demonstrates that Berberine reduces the tumor recurrence rate of NNMTlow/DNMT1high colorectal adenomas.

Practical Implications

Biomarker Identification

NNMT and DNMT1 can be used as biomarkers for selecting cancer patients suitable for therapies targeting the mitochondrial OXPHOS pathway.

Therapeutic Target

The NNMT-DNMT1 axis can be a potential therapeutic target for modulating cancer cell sensitivity to OXPHOS inhibition.

Personalized Medicine

Assessing the NNMT/DNMT1 status in cancer cells could help predict the response to OXPHOS-targeting therapies like Berberine.

Study Limitations

1
The direct NNMT/DNMT1 target(s) essential for cancer cell sensitivity to OXPHOS inhibition remain largely unknown and need further exploration.
2
Enhanced DNMT1 activity itself is not able to create a genome-wide DNA methylation status sufficient for altering cancer cells’ sensitivity to OXPHOS inhibition.
3
The precise mechanism for cancer OXPHOS dependency remains elusive and excellent biomarkers are still lacking, which greatly limits the development of novel cancer therapies by applying mitochondrial OXPHOS inhibitors.

Your Feedback

Was this summary helpful?

Back to Oncology