RhoA WT allele loss unleashes the cancer driver function of RhoA E40Q
Justine Noujarède, Qiuyue Wang, Eleftherios Panagiotis Kokkinogenis, Yuewan Luo, Ivona Cudina, Simon Willaume, Clémence Mooser, Lap Phuoc Nguyen, Mads Frederik Poulsen, Simon Heijmerikx, Thu Han Le Phan, Xiubin He, Jesper Bøje Andersen, Claus Storgaard Sørensen, Cord Brakebusch
Justine Noujarède, Qiuyue Wang, Eleftherios Panagiotis Kokkinogenis, Yuewan Luo, Ivona Cudina, Simon Willaume, Clémence Mooser, Lap Phuoc Nguyen, Mads Frederik Poulsen, Simon Heijmerikx, Thu Han Le Phan, Xiubin He, Jesper Bøje Andersen, Claus Storgaard Sørensen, Cord Brakebusch
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Research Article Cell biology Oncology

RhoA WT allele loss unleashes the cancer driver function of RhoA E40Q

Abstract

Cancer hot spot mutations of unknown function often obscure the functional understanding of the molecular pathways underlying cancer formation and limit the progress of precision medicine. We investigated unresolved driver functions of RHOA in head and neck squamous cell carcinoma. Our investigation reveals that RHOA E40Q is a partial loss-of-function allele that paradoxically promotes tumorigenesis only in the absence of WT RhoA. Therefore, mice expressing RHOA E40Q specifically in keratinocytes lacking WT Rhoa spontaneously developed squamous cell carcinoma and had defective hair shaft formation. Mechanistically, this is related to increased replication stress and genome instability caused by aberrant expression of cell cycle regulators and DNA repair genes, independent of the classical RhoA effectors ROCK and DIAPH. These data establish RHOA E40Q as an unusual, context-dependent oncogenic driver: a seemingly inactive variant that unleashes its tumor-promoting potential only when the WT allele is absent.

Authors

Justine Noujarède, Qiuyue Wang, Eleftherios Panagiotis Kokkinogenis, Yuewan Luo, Ivona Cudina, Simon Willaume, Clémence Mooser, Lap Phuoc Nguyen, Mads Frederik Poulsen, Simon Heijmerikx, Thu Han Le Phan, Xiubin He, Jesper Bøje Andersen, Claus Storgaard Sørensen, Cord Brakebusch

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Figure 1

RHOA E40Q has similar signaling effects as RHOA KO.

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RHOA E40Q has similar signaling effects as RHOA KO. Quantification and ...
Quantification and representative examples of Western blots for RhoA, RhoB, pMLC, and GAPDH (loading control) with indicated cell types. Shown are WT cells transduced with empty vector (empty), or RHOA KO transduced with empty vector, RHOA WT (WT), or E40Q. Data are shown as fold change relative to RHOA KO + RHOA WT. Error bars represent SD of the mean. (A) H376 (n = 13–17), SCC12 (n = 8), SCC27 (n = 6), and CJM (n = 8). Statistical significance was determined using 1-way ANOVA. (B) Quantification of RhoB expression in RHOA KO cells transduced with RHOA E40Q relative to RhoB expression in RhoA KO cells. Statistical significance was assessed using an unpaired t test. (C) As additional cell types, RHOA KO + RHOA WT and E40Q with a RHOB KO were tested. H376 (n = 8–11), CJM (n = 4). The data for WT and RHOA KO for these figures are also included in A. Statistical significance was determined using 1-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.