Xiamen University scholar Nature published a paper: METTL3 acetylation modification regulates its nucleoplasmic dynamic transposition and affects the mechanism of breast cancer metastasis

The methyltransferase METTL3 (methyltransferase like 3) is responsible for the N6-adenosine methyl modification (^m6A) of mRNA, which regulates gene expression and protein translation through a variety of mechanisms, and is widely involved in regulating cell life activities and the occurrence and development of a variety of
diseases.
METTL3 has long been considered a classical nuclear protein
.
Does it have cytoplasmic localization? What is the regulatory mechanism and function of nuclear translocation? It is not clear
.

Recently, Professor You Han's research team published a research paper
entitled METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions in Nature Communications.
This study revealed the molecular mechanism
by which acetylation modifications dynamically regulate the nucleoplasmic localization of METTL3 and tumor invasion and metastasis.

The team found in a variety of tumor cell lines and clinical tumor tissue samples that the METTL3 nucleoplasmic distribution law is highly correlated
with the invasion and metastasis potential of tumors.
Among the tumor cells with high metastasis, METTL3 is mainly distributed in the nucleus; In low/non-metastatic tumor cells, METTL3 is dominated
by cytoplasmic distribution.
The study further found that: METTL3 acetylation modification led to differences in its nucleoplasm distribution; p300 and SIRT1 are responsible for acetylation/deacetylation modification of METTL3 K177 sites, respectively.
Acetylation weakens METTL3 nucleation and blocks it in the cytoplasm, resulting in a significant decrease in the overall modification level of transcriptome^m6A.
Among them, the pro-transfer-related genes (including IL-6, etc.
) were significantly down-regulated.
However, acetylation-induced METTL3 cytoplasmic localization can significantly promote protein translation and upregulate the expression level
of proteins that inhibit metastasis.
This work also revealed that IL-6 in the tumor microenvironment can activate the AMPK-SIRT1 signaling pathway, promote METTL3 deacetylation and nucleation, significantly adjust the level of somatic^m6A, and further increase IL-6 expression, thereby forming a positive feedback loop
.
This positive feedback regulatory loop is critical
for tumor metastasis.
Using animal models of graft tumors, the team also found that the combination of aspirin (ASP) and nicotinamide (NAM) could inhibit tumor metastasis
by acetylating METTL3.

This work reveals the mechanism and function of METTL3 nucleoplasmic translocation for the first time.
Resolve the mechanism by which inflammatory signals affect tumor metastasis by regulating epitranscriptional modifications; Elucidating the potential of ASP/NAM drug combinations in anti-tumor metastasis and their molecular mechanisms
.

Li Yuanpei and He Xianiu, doctoral students of the School of Life Sciences, Xiamen University, are the co-first authors
of the paper.
Professor You Han, School of Life Sciences, Xiamen University, is the corresponding author
of the paper.

Original link: style="text-indent: 2em;">(Photo/Text You Han Research Group)