The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer

Liu, Xiaochen; Cui, Jianfeng; Gong, Li; Tian, Fei; Shen, Yajuan; Chen, Lipeng; Wang, Yong; Xia, Yangyang; Liu, Lei; Xiang, Yu‐Tao; Wang, Molin; Jiang, Baichun; Shao, Changshun; Zou, Yongxin; Gong, Yaoqin

doi:10.1038/s41388-020-1236-1

Cited by 30 publications

(42 citation statements)

References 47 publications

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“…CUL4B has been shown to participate in several cancer-associated processes including chemoresistance. Disturbing CUL4B expression could increase sensitivity to chemotherapy in lymphoblastoid cells, non-small-cell lung cancer cells, osteosarcoma and bladder cancer cells ( 29 , 39 , 40 ). Though CUL4B was reported to be involved in the proliferation and migration of GBM cells ( 41 ), the role and mechanism of CUL4B in TMZ resistance have rarely been studied.…”

Section: Discussionmentioning

confidence: 99%

“…All the media were supplemented with 10% fetal bovine serum (FBS), and all cell cultures were maintained at 37°C in a 5% CO 2 incubator. CUL4B stable knockdown, stable overexpressed, and control cells were generated as previously described ( 29 , 42 ). p21 overexpression plasmid was purchased from Shanghai Jikai Gene Co., Ltd. Transfection of plasmids was performed according to standard protocols using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Colony formation assays were employed to measure the sensitivity of TMZ. The CCK-8 and colony formation assays were performed as previously described ( 29 ). For CCK-8 assays, 1 × 10 3 cells per well were plated into a 96-well plate.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have demonstrated that CUL4B is related to chemoresistance in lymphoblastoid cells, non-small-cell lung cancer cells, osteosarcoma and bladder cancer cells ( 29 , 39 , 40 ). It has been reported that CUL4B promotes proliferation of glioma cells ( 41 ).…”

Section: Introductionmentioning

confidence: 99%

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CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription

et al. 2021

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Resistance to temozolomide (TMZ), the first-line chemotherapeutic drug for glioblastoma (GBM) and anaplastic gliomas, is one of the most significant obstacles in clinical treatment. TMZ resistance is regulated by complex genetic and epigenetic networks. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. CUL4B has been shown to be upregulated and promotes progression and chemoresistance in several cancer types. However, its regulatory effect and mechanisms on TMZ resistance have not been elucidated. The aim of this study was to decipher the role and mechanism of CUL4B in TMZ resistance. Western blot and public datasets analysis showed that CUL4B was upregulated in glioma specimens. CUL4B elevation positively correlated with advanced pathological stage, tumor recurrence, malignant molecular subtype and poor survival in glioma patients receiving TMZ treatment. CUL4B expression was correlated with TMZ resistance in GBM cell lines. Knocking down CUL4B restored TMZ sensitivity, while upregulation of CUL4B promoted TMZ resistance in GBM cells. By employing senescence β-galactosidase staining, quantitative reverse transcription PCR and Chromatin immunoprecipitation experiments, we found that CUL4B coordinated histone deacetylase (HDAC) to co-occupy the CDKN1A promoter and epigenetically silenced CDKN1A transcription, leading to attenuation of TMZ-induced senescence and rendering the GBM cells TMZ resistance. Collectively, our findings identify a novel mechanism by which GBM cells develop resistance to TMZ and suggest that CUL4B inhibition may be beneficial for overcoming resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription

et al. 2021

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“…CUL4B is dysregulated in various tumors and participates in many cellular processes related to tumors [28]. CUL4B functions as a carcinogen in diverse tumors, including bladder cancer [29], colorectal cancer [30] and lung adenocarcinoma [31]. In ovarian cancer, CUL4B was overtly up-regulated in cancer tissues and CUL4B facilitated cancer cell proliferation by mediating CDK2 and CyclinD1 [32].…”

Section: Discussionmentioning

confidence: 99%

Circ_0015756 promotes the progression of ovarian cancer by regulating miR-942-5p/CUL4B pathway

Wang

2020

Cancer Cell Int

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Background Ovarian cancer (OC) is the gynecologic cancer with the highest mortality. Circular RNAs (circRNAs) play a vital role in the development and progression of cancer. This study aimed to explore the potential role of circ_0015756 in OC and its molecular mechanism. Methods The levels of circ_0015756, microRNA-942-5p (miR-942-5p) and Cullin 4B (CUL4B) were determined by quantitative real-time PCR (qRT-PCR) or Western blot assay. Cell proliferation, apoptosis, migration and invasion were assessed by Cell Counting Kit-8 (CCK-8), colony formation assay, flow cytometry and transwell assay. The levels of proliferation-related and metastasis-related proteins were measured by Western blot assay. The relationship between miR-942-5p and circ_0015756 or CUL4B was verified by dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. Xenograft assay was used to analyze tumor growth in vivo. Results Circ_0015756 and CUL4B levels were increased, while miR-942-5p level was decreased in OC tissues and cells. Depletion of circ_0015756 suppressed proliferation, migration and invasion and promoted apoptosis in OC cells. Down-regulation of circ_0015756 hindered OC cell progression via modulating miR-942-5p. Also, up-regulation of miR-942-5p impeded OC cell development by targeting CUL4B. Mechanistically, circ_0015756 up-regulated CUL4B via sponging miR-942-5p. Moreover, circ_0015756 silencing inhibited tumor growth in vivo. Conclusion Knockdown of circ_0015756 suppressed OC progression via regulating miR-942-5p/CUL4B axis, suggesting that circ_0015756 might be a potential therapeutic target for ovarian cancer.

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Transitional cell carcinoma matrix stiffness regulates the osteopontin and YAP expression in recurrent patients

et al. 2021

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The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer

Cited by 30 publications

References 47 publications

CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription

CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription

Circ_0015756 promotes the progression of ovarian cancer by regulating miR-942-5p/CUL4B pathway

Transitional cell carcinoma matrix stiffness regulates the osteopontin and YAP expression in recurrent patients

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