Abstract
The association of RNA modification in cancer has recently been highlighted. Methyltransferase like 8 (METTL8) is an enzyme and its role in mRNA m3C modification has barely been studied. In this study, we found that METTL8 expression was significantly up-regulated in canine mammary tumor and investigated its functional roles in the tumor process, including cancer cell proliferation and migration. METTL8 expression was up-regulated in most human breast cancer cell lines tested and decreased by Yin Yang 1 (YY1) transcription factor knockdown, suggesting that YY1 is a regulating transcription factor. The knockdown of METTL8 attenuated tumor cell growth and strongly blocked tumor cell migration. AT-rich interactive domain-containing protein 1A (ARID1A) was identified as a candidate mRNA by METTL8. ARID1A mRNA binds to METTL8 protein. ARID1A mRNA expression was not changed by METTL8 knockdown, but ARID1A protein level was significantly increased. Collectively, our study indicates that METTL8 up-regulated by YY1 in breast cancer plays an important role in cancer cell migration through the mRNA modification of ARID1A, resulting in the attenuation of its translation.
Highlights
Breast cancer is the most commonly diagnosed cancer in women around the world and is a major cause of cancer-related death
Our results suggest that the Yin Yang 1 (YY1)-Methyltransferase like 8 (METTL8)-AT-rich interactive domain-containing protein 1A (ARID1A) axis has an important role in breast cancer migration as well as in proliferation
We analyzed the expression levels of the genes that have been identified as RNA modification-associated functions from the transcriptome data of canine mammary tumor and adjacent normal tissue [17]
Summary
Breast cancer is the most commonly diagnosed cancer in women around the world and is a major cause of cancer-related death. In breast cancer, overexpressed METTL3 has been shown to increase HBXIP mRNA methylation, thereby promoting breast cancer cell proliferation [9]. A few recent studies have reported that mRNA modification does not play a role as cancer driver, but is known to be associated with cancer survival, growth, and differentiation [12]. More research on its functions and regulation is mandatory because major regulators and target RNAs might be varied in different cells and conditions. The cancer cell migration and proliferation functions of METTL8 that increase the mortality rate and promote metastasis in breast cancer have not been demonstrated yet [14,15,16]. Our results suggest that the YY1-METTL8-ARID1A axis has an important role in breast cancer migration as well as in proliferation
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