MICAL1 regulates actin cytoskeleton organization, directional cell migration and the growth of human breast cancer cells as orthotopic xenograft tumours

McGarry, D. J., Armstrong, G., Castino, G., Mason, S., Clark, W., Shaw, R., McGarry, L., Blyth, K. and Olson, M. F. (2021) MICAL1 regulates actin cytoskeleton organization, directional cell migration and the growth of human breast cancer cells as orthotopic xenograft tumours. Cancer Letters, 519, pp. 226-236. (doi: 10.1016/j.canlet.2021.07.039) (PMID:34314753)

Abstract

The Molecule Interacting with CasL 1 (MICAL1) monooxygenase has emerged as an important regulator of cytoskeleton organization via actin oxidation. Although filamentous actin (F-actin) increases MICAL1 monooxygenase activity, hydrogen peroxide (H2O2) is also generated in the absence of F-actin, suggesting that diffusible H2O2 might have additional functions. MICAL1 gene disruption by CRISPR/Cas9 in MDA MB 231 human breast cancer cells knocked out (KO) protein expression, which affected F-actin organization, cell size and motility. Transcriptomic profiling revealed that MICAL1 deletion significantly affected the expression of over 700 genes, with the majority being reduced in their expression levels. In addition, the absolute magnitudes of reduced gene expression were significantly greater than the magnitudes of increased gene expression. Gene set enrichment analysis (GSEA) identified receptor regulator activity as the most significant negatively enriched molecular function gene set. The prominent influence exerted by MICAL1 on F-actin structures was also associated with changes in the expression of several serum-response factor (SRF) regulated genes in KO cells. Moreover, MICAL1 disruption attenuated breast cancer tumour growth in vivo. Elevated MICAL1 gene expression was observed in invasive breast cancer samples from human patients relative to normal tissue, while MICAL1 amplification or point mutations were associated with reduced progression free survival. Collectively, these results demonstrate that MICAL1 gene disruption altered cytoskeleton organization, cell morphology and migration, gene expression, and impaired tumour growth in an orthotopic in vivo breast cancer model, suggesting that pharmacological MICAL1 inhibition could have therapeutic benefits for cancer patients.

• Item Type: Articles
• Additional Information: This research was supported by CRUK institutional funding to the CRUK Beatson Institute (A10419, A17196), to the Blyth lab (A29799), and to the Olson lab (A18276). Additional funding to M.F.O from the Canadian Institutes of Health Research (PJT-169125), Natural Sciences and Engineering Research Council of Canada (RGPIN-2020-05388), Canada Research Chairs Program (950–231665), and the Ryerson University Faculty of Science Dean's Research Fund.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mason, Miss Susan and McGarry, Ms Lynn and Clark, Mr William and Blyth, Professor Karen and Olson, Professor Michael

Creator Roles

Mason, S.: Data curation, Investigation, Methodology
Clark, W.: Investigation, Methodology, Resources
McGarry, L.: Data curation, Formal analysis, Investigation, Methodology
Blyth, K.: Data curation, Resources, Supervision, Writing – review and editing
Olson, M. F.: Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Visualization, Writing – original draft

• Authors: McGarry, D. J., Armstrong, G., Castino, G., Mason, S., Clark, W., Shaw, R., McGarry, L., Blyth, K., and Olson, M. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Letters
• Publisher: Elsevier
• ISSN: 0304-3835
• ISSN (Online): 1872-7980
• Published Online: 24 July 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cancer Letters 519:226-236
• Publisher Policy: Reproduced under a Creative Commons Licence