You Han's team at Xiamen University discovered that acetylation modifications dynamically regulate the nucleoplasmic localization of oncogenigens and the molecular mechanism of tumor invasion and metastasis

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Written by Mia

Methyltransferase-like 3 (METTL3) is widely recognized as a nucleoprotein
with carcinogenic properties.
In human cancer, mainly cytoplasmic METTL3 expression is negatively correlated
with lymph node metastasis.
In terms of driving tumorigenesis, we currently do not know whether nuclear METTL3 is functionally different from the cytosolic METTL3, and if so, how tumor cells sense carcinogenic damage and thus coordinate METTL3 function in these intracellular compartments
.

On October 26, 2022, the team of You Han of Xiamen University published a research paper
entitled "METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions" in Nature Communications 。 The study identified an acetylation-dependent regulatory mechanism that determines METTL3 subcellular localization, which may provide mechanistic clues
for the development of therapeutic strategies against breast cancer metastasis.

https://doi.
org/10.
1038/s41467-022-34209-5

Research background

 01 

There is growing evidence that^m6Amodifications are involved in regulating a wide range of biological events, including mRNA turnover, RNA splicing, gene transcription, and protein translation
.
Thus, dysregulated^m6Ahomeostasis may affect various pathophysiological processes, leading to altered cell fate decisions as well as human disease
.
Studies have found that a multi-protein complex, including METTL3, METL14, WTAP and several additional subunits, can catalyze m6A methylation
on thousands of ploy(A⁾⁺ transcripts.
Structural analysis showed that METTL3 served as the catalytic core and METTL14 as the RNA-binding platform
.
WTAP targeted METTL3 and METTL14 as nuclear spots
.

In addition to catalyzing^m6Amodifications, METTL3 regulates gene transcription or protein translation
through different mechanisms.
For example, cytoplasmically localized METTL3 can facilitate protein translation in an m6A-independent manner, but requires eIF3h via the mRNA looping mechanism, while promoter-bound METTL3 can facilitate protein translation
by alleviating ribosome arrest in an^{m6A-dependent}manner.
These studies suggest that the subcellular distribution of METTL3 is a fundamental determinant of
its physiological function.
The localization of METTL3 depends on the cell type and stress type
.
However, the molecular determinants of METTL3's dynamic subcellular localization and their functional consequences
are not yet well understood.

The role of METTL3 in tumorigenicity has been extensively studied
.
A large number of studies have shown that the depletion of METTL3 inhibits cell viability and inhibits tumorigenesis
.
In this paper, the research team analyzed the significant role
of acetylation in regulating METTL3 localization and its subsequent effect on tumorigenic progression.

Overview of the study

 02 

The research team found that the distribution of METTL3 nucleoplasm is highly correlated
with the invasion and metastasis potential of tumors in a variety of tumor cell lines and clinical tumor tissue samples.
In highly metastatic tumor cells, METTL3 is dominated by nuclear distribution.
In low/non-metastatic tumor cells, METTL3 is dominated
by cytoplasmic distribution.

Further studies found that METTL3 acetylation modification led to differences
in its nucleoplasm distribution.
After screening, p300 can be used as a physiological acetyltransferase for METTL3, while K177 is the main acetylation site on p300-modified METTL3
.
In addition, SIRT1 knockdown profoundly promotes endogenous METTL3 acetylation and is the physiological deacetylase
of METTL3.

Acetylation weakens METTL3 nucleation, blocking it in the cytoplasm, resulting in a significant reduction
in the overall modification level of transcriptome^m6A.
Among them, the pro-metastasis-related genes (including IL-6, etc.
) were significantly down-regulated, but the acetylation-induced METTL3 cytoplasmic localization could significantly promote protein translation and upregulate the expression level
of proteins that inhibit metastasis.

The team also identified an IL-6-dependent positive feedback axis that promotes nuclear METTL3 function and triggers breast cancer metastasis
.
The mRNA transcript of IL-6 is modified by METTL3-mediated m6A, which promotes METTL3 deacetylation and nuclear transposition, thereby inducing overall^m6Aabundance
.
This deacetylation-mediated METTL3 nuclear transfer can be counteracted
by SIRT1 inhibition.
In addition, in animal models of transplanted tumors, the combination of aspirin (ASP) and nicotinamide (NAM) inhibits tumor metastasis
by acetylating METTL3.

METTL3 acetylation stops cancer metastasis by fine-tuning its nuclear and cytosolic functions

Resources:

https://doi.
org/10.
1038/s41467-022-34209-5

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.

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