m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer

By J. Liu, Mark A. Eckert, Bryan T. Harada, Song-Mei Liu, Zhike Lu, Kangkang Yu, Samantha M. Tienda, Agnieszka Chryplewicz, Allen C. Zhu, Ying Yang and 10 more. Nature Cell Biology, 2018

667 citations recorded by the source corpus.

N6-methyladenosine (m6A) messenger RNA methylation is a gene regulatory mechanism affecting cell differentiation and proliferation in development and cancer. To study the roles of m6A mRNA methylation in cell proliferation and tumorigenicity, we investigated human endometrial cancer in which a hotspot R298P mutation is present in a key component of the methyltransferase complex (METTL14). We found that about 70% of endometrial tumours exhibit reductions in m6A methylation that are probably due to either this METTL14 mutation or reduced expression of METTL3, another component of the methyltransferase complex. These changes lead to increased proliferation and tumorigenicity of endometrial cancer cells, likely through activation of the AKT pathway. Reductions in m6A methylation lead to decreased expression of the negative AKT regulator PHLPP2 and increased expression of the positive AKT regulator mTORC2. Together, these results reveal reduced m6A mRNA methylation as an oncogenic mechanism in endometrial cancer and identify m6A methylation as a regulator of AKT signalling. Liu et al. show that reduced m6A mRNA methylation in endometrial cancer is oncogenic. Mechanistically, the AKT pathway is activated in these tumours due to altered expression of AKT regulators carrying m6A on their transcripts.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9136992d6d9c036f7610c91981083e43843e708d

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Chuan He
2. P. He
3. Hailing Shi
4. Huayan Duan
5. Yuanyuan An
6. Samie R. Jaffrey

In Molecular Biology

1. Chuan He
2. P. He
3. Samie R. Jaffrey
4. S. Zaccara
5. Hailing Shi
6. Jiangbo W
7. Syuzo Kaneko
8. Masaaki Komatsu

Citations in the corpus

• A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA (2020, background): “An important concept in m6A-mediated gene regulation is that the different DF proteins bind distinct subsets of m6A residues in the transcriptome (Han et al., 2019; Liu et al., 2018; Shi et al., 2017; Shi et al., 2019; Shi et al., 2018; Wang et al., 2015).”
• The role of m6A RNA methylation in cancer metabolism (2022, background): “It is found that PHLPP2 is the target of YTHDF1, and YTHDF1 promotes the translation of m6A methylated transcript, while mTORC2 is the target of YTHDF2, and YTHDF2 promotes the decay of m6A methylated transcription [21, 34, 35] (Fig.”
• The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “The decrease in m6A methylation decreased the expression of the negative AKT regulator PHLPP2 and increased the expression of the positive AKT regulator mTORC2 [80].”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “However, in the case of endometrial cancer cells, YTHDF1 and YTHDF2 clearly target unique transcripts and respectively regulate mRNA translation and decay (Liu et al., 2018).”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “Loss of METTL14 increases the proliferation and tumorigenicity of endometrial cancer cells by altering the mRNA stability and translation of AKT pathway regulators (Liu et al , 2018). m 6 A has also been reported to play tumor suppressor roles in renal cell carcinoma (Li et al , 2017b).”
• Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, background): “Notably, low levels of m6A in mRNA enhanced endometrial cancer cell proliferation and tumorigenicity via AKT serine/threonine kinase (AKT) signaling [91].”