Effects of SETD2 on telomere length and malignant transformation property of Met-5A after one-month crocidolite exposure

Abstract

Crocidolite is a carcinogen contributing to the pathogenesis of malignant mesothelioma. This study aimed to characterize the possible telomere-related events mediating the malignant transformation of mesothelial cells with and without SETD2 under crocidolite exposure. The crocidolite concentration resulting in 90% viable SETD2 knockout Met-5A (Met-5A^SETD2-KO) and Met-5A were estimated to be 0.71 μg/cm² and 1.8 μg/cm², respectively, during 72 h of exposure, which was further employed in chronical crocidolite exposure during a 72 h exposure interval per time up to 1 month. Chronical crocidolite-exposed Met-5A^SETD2-KO (chronical Cro-Met-5A^SETD2-KO) had higher colony formation and increased telomerase reverse transcriptase (TERT) protein levels than chronical crocidolite-exposed Met-5A (chronical Cro-Met-5A) and Met-5A^SETD2-KO. Chronical Cro-Met-5A^SETD2-KO had longer telomere length (TL) than chronical Cro-Met-5A, although there were no changes in TL for either chronical Cro-Met-5A or chronical Cro-Met-5A^SETD2-KO compared with their corresponding cells without crocidolite exposure. BIBR 1532, an inhibitor targeting TERT, partially reduced colony formation and TL for chronical Cro-Met-5A^SETD2-KO, while BIBR 1532 reduced TL but had no effect on colony formation for chronical Cro-Met-5A. Therefore, SETD2 deficient mesothelial cells are susceptible to malignant transformation during chronical crocidolite exposure, and TERT-dependent TL modification likely partially drives SETD2 loss-mediated early onset of mesothelial malignant transformation.

Keywords:

• Asbestos
• malignant transformation
• mesothelioma
• SETD2
• telomerase reverse transcriptase

Acknowledgments

This study was partially funded by the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No. LBY21H240001, and the Zhejiang Provincial Medical & Health Science and Technology Project under Grant No. 2022KY728 and Grant No. 2020KY100. The sponsor had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Disclosure statement

None to declare.

Data availability statement

All data are within the manuscript.