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Tumor-derived ARHGAP35 mutations enhance the Gα13-Rho signaling axis in human endometrial cancer

Cancer Gene Therapy volume 30, pages 313–323 (2023)Cite this article

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Abstract

Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα13 is highly expressed in various cancers and regulates diverse cancer-related transcriptional networks and cellular functions by activating Rho. Herein, we demonstrate that increased expression of Gα13 promotes cell proliferation through activation of Rho and the transcription factor AP-1 in human endometrial cancer. Of interest, the RhoGTPase activating protein (RhoGAP), ARHGAP35 is frequently mutated in human endometrial cancers. Among the 509 endometrial cancer samples in The Cancer Genome Atlas database, 108 harbor 152 mutations at 126 different positions within ARHGAP35, representing a somatic mutation frequency of 20.2%. We evaluated the effect of 124 tumor-derived ARHGAP35 mutations on Gα13-mediated Rho and AP-1 activation. The RhoGAP activity of ARHGAP35 was impaired by 55 of 124 tumor-derived mutations, comprised of 23 nonsense, 15 frame-shift, 15 missense mutations, and two in-frame deletions. Considering that ARHGAP35 is mutated in >2% of all tumors, it ranks among the top 30 most significantly mutated genes in human cancer. Our data suggest potential roles of ARHGAP35 as an oncogenic driver gene, providing novel therapeutic opportunities for endometrial cancer.

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Fig. 1: Gα13 expression in human endometrial tissues.
Fig. 2: Gα13 expression promotes cell proliferation and AP-1 activation in human endometrial cells.
Fig. 3: Gα13 activation is involved in AP-1 activation.
Fig. 4: Rho inhibition perturbed Gα13-mediated AP-1 activation.
Fig. 5: The role of ARHGAP35 in Gα13-induced Rho and AP-1 activation.
Fig. 6: The effects of tumor-derived ARHGAP35 mutations on Gα13-induced activation of Rho and AP-1 and foci formation.

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Data availability

The endometrial cancer patient data were generated by TCGA and downloaded with cBioportal (www.cbioportal.com).

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Acknowledgements

We are grateful to Ms. Michiyo Okada and the Research Support Center, Graduate School of Medical Science, Kyushu University for technical support. We also thank James P. Mahaffey, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. This study was supported in part by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (21K09496).

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  1. Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Hiroshi Yagi, Ichiro Onoyama, Kazuo Asanoma, Minoru Kawakami, Shoji Maenohara, Keisuke Kodama, Yumiko Matsumura, Norio Hamada, Emiko Hori, Kazuhisa Hachisuga, Masafumi Yasunaga, Tatsuhiro Ohgami, Kaoru Okugawa, Hideaki Yahata & Kiyoko Kato

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Contributions

HY and KK designed research; HY and EH performed experiments; IO, KA, MK, SM, KK, YM and NH analyzed data; KH, MY, TO, KO and HY interpreted results of experiments; HY prepared figures; HY and KK drafted and edited the manuscript.

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Correspondence to Hiroshi Yagi.

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Yagi, H., Onoyama, I., Asanoma, K. et al. Tumor-derived ARHGAP35 mutations enhance the Gα13-Rho signaling axis in human endometrial cancer. Cancer Gene Ther 30, 313–323 (2023). https://doi.org/10.1038/s41417-022-00547-1

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