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Identification of DHX36 as a tumour suppressor through modulating the activities of the stress-associated proteins and cyclin-dependent kinases in breast cancer

Zeng, Yinduo, Tao, Qin, Flamini, Valentina, Tan, Cui, Zhang, Xinke, Cong, Yizi, Birkin, Emily, Jiang, Wen G., Yao, Herui and Cui, Yuxin 2020. Identification of DHX36 as a tumour suppressor through modulating the activities of the stress-associated proteins and cyclin-dependent kinases in breast cancer. American Journal of Cancer Research 10 (12) , pp. 4211-4233.

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Abstract

The nucleic acid guanine-quadruplex structures (G4s) are involved in many aspects of cancer progression. The DEAH-box polypeptide 36 (DHX36) has been identified as a dominant nucleic acid helicase which targets and disrupts DNA and RNA G4s in an ATP-dependent manner. However, the actual role of DHX36 in breast cancer remains unknown. In this study, we observed that the gene expression of DHX36 was positively associated with patient survival in breast cancer. The abundance of DHX36 is also linked with pathologic conditions and the stage of breast cancer. By using the xenograft mouse model, we demonstrated that the stable knockdown of DHX36 via lentivirus in breast cancer cells significantly promoted tumour growth. We also found that, after the DHX36 knockdown (KD), the invasion of triple-negative breast cancer cells was enhanced. In addition, we found a significant increase in the number of cells in the S-phase and a reduction of apoptosis with the response to cisplatin. DHX36 KD also desensitized the cytotoxic cellular response to paclitaxel and cisplatin. Transcriptomic profiling analysis by RNA sequencing indicated that DHX36 altered gene expression profile through the upstream activation of TNF, IFNγ, NFκb and TGFβ1. High throughput signalling analysis showed that one cluster of stress-associated kinase proteins including p53, ROCK1 and JNK were suppressed, while the mitotic checkpoint protein-serine kinases CDK1 and CDK2 were activated, as a consequence of the DHX36 knockdown. Our study reveals that DHX36 functions as a tumour suppressor and may be considered as a potential therapeutic target in breast cancer.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: e-Century Publishing
ISSN: 2156-6976
Funders: Cancer Research Wales, Cardiff China Medical Scholarship, Life Sciences Research Network Wales, the National Natural Science Foundation of China(81572596?U1601223, 81502302), and grants from the Guangdong Natural Science Foundation (2017A030313828, 2017A030313489), and funding from the Guangzhou Science and Technology Bureau (201704020131). China Scholarship Council (CSC)
Date of First Compliant Deposit: 1 December 2020
Date of Acceptance: 28 November 2020
Last Modified: 21 Oct 2021 01:39
URI: http://orca.cardiff.ac.uk/id/eprint/136684

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