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Elevated TRIP13 drives cell proliferation and drug resistance in bladder cancer.

ABSTRACT: Dysregulation of mitotic processes can induce chromosome instability, which results in aneuploidy, tumorigenesis, and chemo-resistance. Thyroid hormone receptor interactor 13 (TRIP13) is a critical mitosis regulator, and recent studies suggest that it functions as an oncogene in multiple cancers. However, the role of TRIP13 in bladder cancer (BC) is still unknown. In this study, our analysis of RNA-sequencing data from the Cancer Genome Atlas and Gene expression profiling databases showed that TRIP13 expression was upregulated in BC tissues, and overexpression of TRIP13 was significantly associated with poor prognosis of BC patients. In addition, we found a remarkable elevation of TRIP13 in BC samples compared to normal controls by immunohistochemistry. Furthermore, our in vitro functional assays showed that overexpression of TRIP13 promoted the growth/viability, colony formation ability by inducing cell cycle arrest in G2/M phase, as well as enhancing drug resistance of BC cells to cisplatin and doxorubicin. Conversely, knockdown of TRIP13 inhibited cell growth and induced apoptosis of BC cells. Furthermore, TRIP13 acted as an oncogene in BC by inhibiting spindle assembly checkpoint signaling by targeting mitotic arrest deficient 2 (MAD2) protein. TRIP13 overexpression also alleviated cisplatin- and doxorubicin-induced DNA damage and enhanced DNA repair as evidenced by the reduced expression of ?H2AX and enhanced expression of RAD50 in drug-treated BC cells. In conclusion, TRIP13 may be a novel target for the treatment of BC.

SUBMITTER: Lu S

PROVIDER: S-EPMC6684882 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Elevated TRIP13 drives cell proliferation and drug resistance in bladder cancer.

Lu Sicheng S Guo Mengjie M Fan Zhimin Z Chen Ying Y Shi Xuqin X Gu Chunyan C Yang Ye Y

American journal of translational research 20190715 7

Dysregulation of mitotic processes can induce chromosome instability, which results in aneuploidy, tumorigenesis, and chemo-resistance. Thyroid hormone receptor interactor 13 (TRIP13) is a critical mitosis regulator, and recent studies suggest that it functions as an oncogene in multiple cancers. However, the role of TRIP13 in bladder cancer (BC) is still unknown. In this study, our analysis of RNA-sequencing data from the Cancer Genome Atlas and Gene expression profiling databases showed that T ...[more]

PMID: 31396344

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Project description:Amplification of chromosomal region 8p11-12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)1-3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful5. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.

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Elevated TRIP13 drives cell proliferation and drug resistance in bladder cancer.

Publications

Elevated TRIP13 drives cell proliferation and drug resistance in bladder cancer.

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