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SETDB1 tumour suppressor roles in near-haploid mesothelioma involve TP53

British Journal of Cancer volume 129, pages 531–540 (2023)Cite this article

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Abstract

Background

Mutational inactivation of the SETDB1 histone methyltransferase is found in a subset of mesothelioma, particularly in cases with near-haploidy and TP53 mutations. However, the tumourigenic consequences of SETDB1 inactivation are poorly understood.

Methods

In this study, we investigated SETDB1 tumour suppressor functions in mesothelioma and explored biologic relationships between SETDB1 and TP53.

Results

Immunoblotting of early passage cultures showed that SETDB1 was undetectable in 7 of 8 near-haploid mesotheliomas whereas SETDB1 expression was retained in each of 13 near-diploid mesotheliomas. TP53 aberrations were present in 5 of 8 near-haploid mesotheliomas compared to 2 of 13 near-diploid mesotheliomas, and BAP1 inactivation was demonstrated only in near-diploid mesotheliomas, indicating that near-haploid and near-diploid mesothelioma have distinct molecular and biologic profiles. Lentiviral SETDB1 restoration in near-haploid mesotheliomas (MESO257 and MESO542) reduced cell viability, colony formation, reactive oxygen species levels, proliferative marker cyclin A expression, and inhibited growth of MESO542 xenografts. The combination of SETDB1 restoration with pemetrexed and/or cisplatin treatment additively inhibited tumour growth in vitro and in vivo. Furthermore, SETDB1 restoration upregulated TP53 expression in MESO542 and MESO257, whereas SETDB1 knockdown inhibited mutant TP53 expression in JMN1B near-haploid mesothelioma cells. Likewise, TP53 knockdown inhibited SETDB1 expression. Similarly, immunoblotting evaluations of ten near-diploid mesothelioma biopsies and analysis of TCGA expression profiles showed that SETDB1 expression levels paralleled TP53 expression.

Conclusion

These findings demonstrate that SETDB1 inactivation in near-haploid mesothelioma is generally associated with complete loss of SETDB1 protein expression and dysregulates TP53 expression. Targeting SETDB1 pathways could be an effective therapeutic strategy in these often untreatable tumours.

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Fig. 1: SETDB1 expression in mesothelioma.
Fig. 2: Evaluations of near-haploid mesothelioma cultures (MESO257 and MESO542) after lentiviral mediated SETDB1 restoration.
Fig. 3: Pemetrexed or cisplatin confers additive anti-proliferative effects in near-haploid mesothelioma after SETDB1 restoration.
Fig. 4: SETDB1 is positively associated with TP53 expression.
Fig. 5: The tumour suppressor roles of SETDB1 associated with TP53 expression were evaluated after TP53 knockdown in near-haploid mesothelioma cells and xenografts with SETDB1 restoration.

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Data availability

All data generated or analysed during this study are included in this published article and its Supplementary Information files.

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Acknowledgements

We thank Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine in Zhejiang Sci-Tech University for providing the experimental platform.

Funding

This research was supported by National Natural Science Foundation of China (82272695), the Key Program of Natural Science Foundation of Zhejiang Province (LZ23H160004), China. This work was also supported by the NIH/NCI SPORE 1P50CA272170-01 (JAF).

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Author notes

  1. These authors contributed equally: Mengting Xu, Yuqing Tu.

Authors and Affiliations

  1. Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China

    Mengting Xu, Yuqing Tu, Wenhui Bi & Wen-Bin Ou

  2. The First Affiliated Hospital of Soochow University, Suzhou, China

    Yuqing Tu

  3. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Meijun Z. Lundberg, Isabella Klooster, Jonathan A. Fletcher & Wen-Bin Ou

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Contributions

WBO and JAF designed the study; MX, YT, WB, MZL, and W-BO performed the experiments and acquired the data. MX, YT, WB, MZL, JAF, and W-BO analysed and interpreted the acquired data. YT, IK, JAF, and WBO participated in scientific discussion and drafting of the manuscript.

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Correspondence to Wen-Bin Ou.

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Brigham and Women’s Hospital and Zhejiang Sci-Tech University Institutional Ethics Boards approved this study. Patients provided informed consent for use of their tissue samples for research purposes. The study was performed in accordance with the Declaration of Helsinki.

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Xu, M., Tu, Y., Bi, W. et al. SETDB1 tumour suppressor roles in near-haploid mesothelioma involve TP53. Br J Cancer 129, 531–540 (2023). https://doi.org/10.1038/s41416-023-02330-x

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