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Bach1 is critical for the transformation of mouse embryonic fibroblasts by RasV12 and maintains ERK signaling

Oncogene volume 32, pages 3231–3245 (2013)Cite this article

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Abstract

Reactive oxygen species (ROS), by-products of aerobic respiration, promote genetic instability and contribute to the malignant transformation of cells. Among the genes related to ROS metabolism, Bach1 is a repressor of the oxidative stress response, and a negative regulator of ROS-induced cellular senescence directed by p53 in higher eukaryotes. While ROS are intimately involved in carcinogenesis, it is not clear whether Bach1 is involved in this process. We found that senescent Bach1-deficient mouse embryonic fibroblasts (MEFs) underwent spontaneous immortalization the same as did the wild-type cells. When transduced with constitutively active Ras (H-RasV12), the proliferation and colony formation of these cells in vitro were markedly reduced. When transplanted into athymic nude mice, the growth and vascularization of tumors derived from Bach1-deficient cells were also decreased. Gene expression profiling of the MEFs revealed a new H-RasV12 signature, which was distinct from the previously reported signatures in epithelial tumors, and was partly dependent on Bach1. The Bach1-deficient cells showed diminished phosphorylation of MEK and ERK1/2 in response to H-RasV12, which was consistent with the alterations in the gene expression profile, including phosphatase genes. Finally, Bach1-deficient mice were less susceptible to 4-nitroquinoline-1-oxidide (4-NQO)-induced tongue carcinoma than wild-type mice. Our data provide evidence for a critical role of Bach1 in cell transformation and tumor growth induced by activated H-RasV12.

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Acknowledgements

We are grateful to Nobuyuki Tanaka from Nippon Medical University and Fuyuki Ishikawa from Kyoto University for kindly providing plasmids. This work was supported by Grants-in-aid and the Network Medicine Global-COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Additional initial support was provided by the Uehara Foundation, the Takeda Foundation and the Astelas Foundation for Research on Metabolic Disorders. Restoration of laboratory damage from the 2011 Tohoku earthquake was provided in part by the Astelas Foundation for Research on Metabolic Disorders, the Banyu Foundation, the Naito Foundation, A Miyazaki and A Iida.

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Authors and Affiliations

  1. Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

    A Nakanome, A Brydun, M Matsumoto, K Ota & K Igarashi

  2. Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan

    A Nakanome, K Shiga & T Kobayashi

  3. Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan

    A Brydun & K Igarashi

  4. Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan

    M Matsumoto

  5. Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan

    R Funayama & K Nakayama

  6. CREST, Japan Science and Technology Agency, Sendai, Japan

    R Funayama & K Igarashi

  7. Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan

    M Ono

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  1. A Nakanome
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Nakanome, A., Brydun, A., Matsumoto, M. et al. Bach1 is critical for the transformation of mouse embryonic fibroblasts by RasV12 and maintains ERK signaling. Oncogene 32, 3231–3245 (2013). https://doi.org/10.1038/onc.2012.336

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