Page 4 - D. Cancer biology

[D. Cancer biology-2]

Metastatic function of METTL18 in breast cancer via actin

methylation and Src

Jieun Oh¹˙#, Han Gyung Kim¹˙#, Yo Han Hong¹, Wooram Choi¹, Deok Jeong¹, Chaoran Song¹, Long You¹,
Jae Youl Cho¹˙*

¹Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea

In this study, we report another type of actin histidine methyltransferase. METTL18 regulates the metastatic potential

of breast cancer in human. Among methyltransferases, METTL18 was highly amplified in human breast cancer. In
particular, poor prognosis was associated with high expression of METTL18 in HER2-negative breast cancer patients.

This gene product was also found to be a critical component of metastatic responses. Loss of METTL18 expression
significantly reduced metastatic responses of breast tumor cells both in vitro and in vivo. Mechanistically, it was

observed that METTL18 increased actin polymerization, upregulated complex formation with HSP90AA1 and Src,
enhanced the activity of an intermediate form of Src with tyrosine phosphorylation at both Y416 and Y527, and

induced cellular metastatic responses, including morphological change, migration, and invasion of MDA-MB-231
cells in vitro and in vivo. Methylated actin at His73 served as a critical site for interaction with HSP90AA1 and Src

to activate p85/PI3K and STAT3. Our findings suggest that METTL18 plays critical roles in metastatic responses of
HER2-negative breast cancer cells via actin polymerization and the generation of an intermediate form of Src.