CRSP8 promotes thyroid cancer progression by antagonizing IKKα-induced cell differentiation

Liao, Yun; Hua, Yi-Jun; Li, Yizhuo; Zhang, Changlin; Yu, Wei; Guo, Ping; Zou, Kun; Li, Wenyang; Sun, Yao; Wang, Ruozhu; Zuo, Yan; Sui, Silei; Tian, Chunfang; Hao, Jie; Chen, Manyu; Hu, Sheng; Chen, Miao; Qian, Long; Wang, Xiaonan; Zou, Lijuan; Xie, Fang‐Yun; Guo, Wei; Deng, Wu

doi:10.1038/s41418-020-00656-0

Cited by 11 publications

(11 citation statements)

References 45 publications

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“…[14][15][16]37 In our previous studies, for the first time, we successively reported the tumor-promoting role of MED27 in melanoma and thyroid cancer by activating the NF-κB/iNOS signaling pathways and antagonizing IKKα-induced cell differentiation, respectively. 13,38 Of note, in terms of the function of MED27 in breast cancer, although a recent report found that MED27 promoted the malignant behavior of cells by affecting Sp1 in breast cancer, 16 its effects were mainly explored for the proliferation and apoptosis of breast cancer cells. As for its role in maintaining breast cancer cell metastasis and stemness and the responsible molecular mechanisms, these points have been relatively unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…Reports regarding the function and the corresponding molecular mechanism of MED27 in tumorigenesis and development are still few. Our previous studies demonstrated the tumor‐promoting role of MED27 in melanoma survival and its dedifferentiation function in thyroid cancer progression 13 . It has also been reported to promote the proliferation and metastasis of adrenal cortical carcinoma cells by affecting the EMT process 14 .…”

Section: Introductionmentioning

confidence: 98%

“…Our previous studies demonstrated the tumor-promoting role of MED27 in melanoma survival and its dedifferentiation function in thyroid cancer progression. 13 It has also been reported to promote the proliferation and metastasis of adrenal cortical carcinoma cells by affecting the EMT process. 14 In addition, microRNA-18a has been found to inhibit the growth of osteosarcoma cells by targeting MED27.…”

Section: Introductionmentioning

confidence: 99%

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MED27 plays a tumor‐promoting role in breast cancer progression by targeting KLF4

Wang

Zhu

et al. 2023

Cancer Science

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The mediator complex usually cooperates with transcription factors to be involved in RNA polymerase II-mediated gene transcription. As one component of this complex, MED27 has been reported in our previous studies to promote thyroid cancer and melanoma progression. However, the precise function of MED27 in breast cancer development remains poorly understood. Here, we found that MED27 was more highly expressed in breast cancer samples than in normal tissues, especially in triple-negative breast cancer, and its expression level was elevated with the increase in pathological stage. MED27 knockdown in triple-negative breast cancer cells inhibited cancer cell metastasis and stemness maintenance, which was accompanied by downregulation of the expression of EMT-and stem traits-associated proteins, and vice versa in non-triple-negative breast cancer. Furthermore, MED27 knockdown sensitized breast cancer cells to epirubicin treatment by inducing cellular apoptosis and reducing tumorsphere-forming ability. Based on RNA-seq, we identified KLF4 as the possible downstream target of MED27. KLF4 overexpression reversed the MED27 silencingmediated arrest of cellular metastasis and stemness maintenance capacity in breast cancer in vitro and in vivo. Mechanistically, MED27 transcriptionally regulated KLF4 by binding to its promoter region at positions −156 to +177. Collectively, our study not only demonstrated the tumor-promoting role of MED27 in breast cancer progression by transcriptionally targeting KLF4, but also suggested the possibility of developing the MED27/KLF4 signaling axis as a potential therapeutic target in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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MED27 plays a tumor‐promoting role in breast cancer progression by targeting KLF4

Wang

Zhu

et al. 2023

Cancer Science

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“…Over the past few decades, thyroid cancer has become an increasingly significant public health issue in most regions of the world [29]. Among thyroid cancers, ATC is a highly lethal cancer, for which treatment strategies have not yet been universally acknowledged, nor is there identified any highly effective treatment option [30]. Hence, the determination of effective treatment agents targeting ATC as well as the discovery of relevant original therapeutic mechanisms are essential to improving the prognosis of ATC patients.…”

Section: Discussionmentioning

confidence: 99%

Anti-Anaplastic Thyroid Cancer (ATC) Effects and Mechanisms of PLX3397 (Pexidartinib), a Multi-Targeted Tyrosine Kinase Inhibitor (TKI)

Luo

Wang

Zhao

et al. 2022

Cancers

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Background Anaplastic thyroid cancer (ATC) is the greatest lethal thyroid neoplasm with a low incidence and lacks an effective treatment strategy and standardized treatment protocol. PLX3397 (Pexidartinib) is an FDA-approved multitarget tyrosine kinase inhibitor. The research is designed to explore the possible anti-proliferative activity of pexidartinib on ATC, as well as its related molecular mechanisms. Methods The cell viability was assessed by CCK-8, LDH release, colony formation, and EdU detection assays. Apoptosis and the alteration on cell cycle arrest were characterized by flow cytometry (FCM). ER stress was evaluated by immunofluorescence (IF). ROS levels were determined by flow cytometry. Western blot assays were conducted to evaluate changes in key molecules related to apoptosis and ER stress. The ATC xenografts model was established, and immunohistochemistry was performed to validate the anti-ATC effects of pexidartinib in vivo. Results Pexidartinib significantly inhibited ATC cell proliferation and induced apoptosis and cell cycle arrest. Moreover, pexidartinib potently induced ER stress and elevated ROS in ATC cells, and the apoptotic cells and ER stress in ATC after administration of pexidartinib could be reversed by an ER stress inhibitor and ROS scavenger, respectively. Furthermore, pexidartinib treatment induced Nrf2 accumulation in nuclei and reduced the interaction of Nrf2 with Keap-1, and knockdown of Nrf2 enhanced the anti-ATC effects of pexidartinib in vitro. In addition, pexidartinib significantly inhibited ATC xenograft growth and proliferation in vivo, and the combination of ML385, an Nrf2 inhibitor, potently enhanced the anti-ATC effects of pexidartinib in vivo. Conclusion Our findings suggest pexidartinib is a potential agent for treating ATC. Co-administration with an Nrf2 inhibitor is an effective synergistic strategy.

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“… 9 An increasing number of studies have demonstrated that EMT activation is closely related to multiple milestones in the development of cancer, including distant metastasis, extrathyroidal extension, and increased cancer cell stemness, and can be observed at the tumor‐stromal boundary of TC. 10 , 11 Due to the complicated process of EMT, which involves various transcriptional and translational factors associated with TC, ancillary diagnostic tools based on standardized genomic characteristics would offer better predictive value than risk stratification based on clinical parameters alone. 12 , 13 Based on the pivotal role of EMT in PTC invasion and anaplastic transformation, we established a novel 10‐gene signature derived from prognosis‐related differentially expressed EMT‐related genes (DE‐ERGs) using Cox proportional hazard analysis.…”

Section: Introductionmentioning

confidence: 99%

A novel prognostic model for papillary thyroid cancer based on epithelial–mesenchymal transition‐related genes

Cao

Pan

et al. 2022

Cancer Medicine

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Background The frequent incidence of postsurgical recurrence issues in papillary thyroid cancer (PTC) patients is a primary concern considering the low cancer‐related mortality. Previous studies have demonstrated that epithelial–mesenchymal transition (EMT) activation is closely related to PTC progression and invasion. In this study, we aimed to develop a novel EMT signature and ancillary nomogram to improve personalized prediction of progression‐free interval (PFI). Methods First, we carried out a differential analysis of PTC samples and pairwise normal thyroid samples to explore the differentially expressed genes (DEGs). The intersection of the DEGs with EMT‐related genes (ERGs) were identified as differentially expressed EMT‐related genes (DE‐ERGs). We determined PFI‐related DE‐ERGs by Cox regression analysis and then established a novel gene classifier by LASSO regression analysis. We validated the signature in external datasets and in multiple cell lines. Further, we used uni‐ and multivariate analyses to identify independent prognostic characters. Results We identified 244 prognosis‐related DE‐ERGs. The 244 DE‐ERGs were associated with several pivotal oncogenic processes. We also constructed a novel 10‐gene signature and relevant prognostic model for recurrence prediction of PTC. The 10‐gene signature had a C‐index of 0.723 and the relevant nomogram had a C‐index of 0.776. The efficacy of the signature and nomogram was satisfying and closely correlated with relevant clinical parameters. Furthermore, the signature also had a unique potential in differentiating anaplastic thyroid cancer (ATC) samples. Conclusions The novel EMT signature and nomogram are useful and convenient for personalized management for thyroid cancer.

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CRSP8 promotes thyroid cancer progression by antagonizing IKKα-induced cell differentiation

Cited by 11 publications

References 45 publications

MED27 plays a tumor‐promoting role in breast cancer progression by targeting KLF4

MED27 plays a tumor‐promoting role in breast cancer progression by targeting KLF4

Anti-Anaplastic Thyroid Cancer (ATC) Effects and Mechanisms of PLX3397 (Pexidartinib), a Multi-Targeted Tyrosine Kinase Inhibitor (TKI)

A novel prognostic model for papillary thyroid cancer based on epithelial–mesenchymal transition‐related genes

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