Metastatic function of METTL18 in breast cancer via actin methylation and Src

Abstract

Recently, a SET domain containing 3 (SETD3) was identified as an actin histidine methyltransferase, functioning to control replication and pathogenesis in multiple mouse models for enterovirus infection as well as the regulation of smooth muscle contractility linked to primary dystocia. Here, in this study, we report another type of actin histidine methyltransferase, METTL18, that 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 mice. 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.

SETD2 is an actin lysine methyltransferase

“…However, it is well known this recombinant actin folds poorly 25 , and we also found it was a poor substrate for SETD2 methylation. Furthermore, a new study (in pre-print) shows histidine 73 methylation of actin by the enzyme METTL18 promotes a metastatic response through Src kinase signaling in HER2-negative breast cancer 26 , demonstrating enzymes other than SETD3 can also methylate actin. Regardless, our data, using purified and recombinant actin proteins sourced from models other than E. coli, clearly demonstrate that SETD2 methylates actin in vivo and in vitro, and lysine methylation is a naturally occurring PTM of the actin cytoskeleton.…”