High Sugar Induced RCC2 Lactylation Drives Breast Cancer Tumorigenicity Through Upregulating MAD2L1

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Lactylation is an emerging post-translational modification involving lactate.
• Its precise regulatory mechanisms and protein targets are not fully understood.
• Understanding lactylation's role in cancer is crucial for developing new therapies.

Purpose of the Study:

• To investigate the role of RCC2 protein in breast cancer progression.
• To elucidate the mechanism by which lactylation affects RCC2.
• To identify potential therapeutic targets for breast cancer.

Main Methods:

• Investigated RCC2 lactylation at K124 mediated by KAT2A.
• Assessed the effect of RCC2 lactylation on SERBP1 recruitment and MAD2L1 mRNA stabilization.
• Utilized a small molecule inhibitor to block RCC2 lactylation and assess its impact on cell proliferation.

Main Results:

• RCC2 lactylation at K124 by KAT2A promotes breast cancer cell proliferation.
• Lactylated RCC2 recruits SERBP1, stabilizing MAD2L1 mRNA and activating the MAD2L1 signaling pathway.
• A small molecule inhibitor targeting RCC2 lactylation reduced breast cancer cell proliferation.

Conclusions:

• RCC2 lactylation is a key mechanism linking metabolism and cell division in breast cancer.
• Targeting RCC2 lactylation presents a novel therapeutic strategy for breast cancer, particularly in high-lactate environments.
• Findings explain MAD2L1 upregulation in high-sugar diet-associated murine tumors.