Page 3 - D. Cancer biology

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

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Jieun Oh , Han Gyung Kim , Yo Han Hong , Wooram Choi , Deok Jeong , Chaoran Song , Long You , and Jae Youl Cho 1
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1 Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea
BACKGROUND AIM
Breast cancer is the most common form of malignant tumor and We examined methylation of histidine (His)-73 residue of actin by
second leading cause of cancer-related deaths in women. Triple METTL18 as a crucial component of metastatic responses of
breast tumor cells through modulation of the actin cytoskeleton and
negative breast cancer (TNBC), accounts for 10 - 15 % of breast Src phosphorylation.
cancer and neither of approved drugs nor established
chemotherapy targeting TNBC at present. METTL18 (histidine METHODS
methyltransferase 1 homolog) is considered a putative human
homolog of YY110W (yeast histidine methyltransferase). B-actin, Immunoblot and realtime PCR were used to detect METTL18
S100A9, myosin, myosin kinase, and ribosomal protein RPL3 expression in cell lines and patient samples. Biological functions of
were known to be methylated at histidine residues and may be METTL18 were examined in vitro and in vivo. Via tumor xenografts,
quite common in intracellular proteins in mammalian cells. metastasis assay and PET/CT, effect of METTL18 in metastatic
However, biological function and molecular characterization of response were analyzed. Immunoprecipitation and mass
METTL18 have yet to be elucidated. spectrometry were conducted to determine the methylation of actin
histidine73 residue.
RESULTS

Here, in this study, we reported 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, overexpressed METTL18 showed
poor prognosis. Knockdown of METTL18
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-MB231 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.
CONCLUSION REFERENCES ACKNOWLEDGEMENTS

This research was supported by the Basic Science
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