Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

PI 3-Kinase and the Histone Methyl-Transferase KMT2D Collaborate to Induce Arp2/3-Dependent Migration of Mammary Epithelial Cells

Karina D Rysenkova
,
Julia Gaboriaud
,
Artem I Fokin
ORCID logo ,
Raphaëlle Toubiana
,
Alexandre Bense
,
Camil Mirdass
,
Mélissa Jin
,
Minh Chau N Ho
,
Elizabeth Glading
,
Sophie Vacher
ORCID logo ,
Laura Courtois
,
Ivan Bièche
,
Alexis M Gautreau
* ORCID logo
Version 1 : Received: 15 February 2024 / Approved: 16 February 2024 / Online: 16 February 2024 (10:12:54 CET)

How to cite: Rysenkova, K.D.; Gaboriaud, J.; Fokin, A.I.; Toubiana, R.; Bense, A.; Mirdass, C.; Jin, M.; Ho, M.C.N.; Glading, E.; Vacher, S.; Courtois, L.; Bièche, I.; Gautreau, A.M. PI 3-Kinase and the Histone Methyl-Transferase KMT2D Collaborate to Induce Arp2/3-Dependent Migration of Mammary Epithelial Cells. Preprints 2024, 2024020907. https://doi.org/10.20944/preprints202402.0907.v1 Rysenkova, K.D.; Gaboriaud, J.; Fokin, A.I.; Toubiana, R.; Bense, A.; Mirdass, C.; Jin, M.; Ho, M.C.N.; Glading, E.; Vacher, S.; Courtois, L.; Bièche, I.; Gautreau, A.M. PI 3-Kinase and the Histone Methyl-Transferase KMT2D Collaborate to Induce Arp2/3-Dependent Migration of Mammary Epithelial Cells. Preprints 2024, 2024020907. https://doi.org/10.20944/preprints202402.0907.v1

Abstract

Breast cancer develops upon sequential acquisition of driver mutations in mammary epithelial cells; however how these mutations collaborate to transform normal cells remains unclear in most cases. We aimed to reconstitute this process in a particular case. To this end, we combined the activated form of the PI 3-kinase harboring the H1047R mutation with the inactivation of the histone lysine methyl-transferase KMT2D in the non-tumorigenic human mammary epithelial cell line MCF10A. We found that PI 3-kinase activation promoted cell cycle progression, especially when growth signals were limiting, as well as cell migration, both in a collective monolayer and as single cells. Furthermore, we showed that KMT2D inactivation had relatively little influence on these processes, except for single cell migration that KMT2D inactivation promoted in synergy with PI 3-kinase activation. Combination of these two genetic alterations induced expression of the ARPC5L gene that encodes a subunit of the Arp2/3 complex. ARPC5L depletion fully abolished the enhanced migration persistence exhibited by double-mutant cells. Our reconstitution approach in MCF10A has thus revealed both the cell function, single cell migration, and the underlying Arp2/3-dependent mechanism, which are synergistically regulated when KMT2D inactivation is combined with the activation of the PI 3-kinase.

Keywords

KMT2D; MLL2; MLL4; PIK3CA; Arp2/3

Subject

Biology and Life Sciences, Cell and Developmental Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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