Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer

Huang, Houbao; Li, Jing; Shen, Jing; Li, Gang; Wu, Xu; Xiang, Shixin; Li, Yawei; Xu, Yujie; Zhao, Qijie; Zhao, Yueshui; Kaboli, Parham Jabbarzadeh; Li, Mingxing; Li, Xiang; Wei-ping, Wang; Wen, Qinglian; Xiao, Zhangang

doi:10.3389/fonc.2020.01474

Cited by 15 publications

(8 citation statements)

References 66 publications

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“…ERRα also mediated chemoresistance of osteosarcoma cells by regulating ABCB1 [17]. Similarly, Huang found that ERRαinduced increased expression of ABCC4 could promote docetaxel e ux and lead to the development of drug resistance in prostate cancer [29]. Collectively, these studies indicate that ERRα plays a critical role in tumor-acquired drug resistance and may serve as a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 83%

Nuclear orphan receptor ERRα promotes cisplatin resistance in breast cancer cells by targeting CCNE2

Liu¹,

Feng

Xuan³

et al. 2022

Preprint

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Background Chemotherapy is one of the most efficient therapeutic methods for cancer, but increasingly serious drug resistance is the main cause of cancer recurrence and treatment failure. Our study aimed to investigate the mechanisms by which upregulation of estrogen-related receptor α (ERRα) induced chemoresistance in breast cancer cells. Methods Immunohistochemistry (IHC) was used to determine the expression of ERRα in breast cancer and adjacent tissues. Functional analyses (in vitro and in vivo) were performed to confirm the role of ERRα in cancerogenesis and cisplatin chemoresistance in breast cancer. RNA-sequencing, ChIP-seq and dual luciferase assays were performed to identify the mechanisms by which ERRα promotes chemoresistance in breast cancer. Results ERRα was highly expressed in breast cancer tissues and the level of ERRα expression was determined to be significantly correlated with the expression level of human epidermal growth factor receptor 2 (HER2). Overexpression of ERRα promoted the proliferation and metastasis of breast cancer in vitro and in vivo while knockdown of ERRα suppressed. Moreover, ERRα was upregulated in chemoresistant breast cancer cells, while ERRα knockdown sensitized cisplatin treatment. Our results further demonstrated that ERRα enhanced the pluripotency of cancer cells and facilitated chemoresistance via upregulating CCNE2 by binding its promoter region. Overexpression of CCNE2 could reverse the sensitivity of breast cancer cells to cisplatin caused by ERRα depletion, thus resulting in accelerated tumor growth. Conclusion We identify that ERRα sustains the chemoresistance of breast cancer cells via regulating the transcription of CCNE2 and may serve as a therapeutic target in breast cancer.

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Section: Discussionmentioning

confidence: 83%

Nuclear orphan receptor ERRα promotes cisplatin resistance in breast cancer cells by targeting CCNE2

Liu¹,

Feng

Xuan³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…ERRα also mediated chemoresistance of osteosarcoma cells by regulating ABCB1 [20]. Similarly, Huang found that ERRαinduced increased expression of ABCC4 could promote docetaxel e ux and lead to the development of drug resistance in prostate cancer [34]. Collectively, these studies indicate that ERRα plays a critical role in tumor-acquired drug resistance and may serve as a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 83%

ERRα confers oncogenesis and cisplatin resistance via transcriptionally activating CCNE2 in breast cancer

Liu

Feng

Xuan

et al. 2022

Preprint

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Background: Platinum is widely used in the neoadjuvant and metastatic treatment of breast cancer, but increasingly drug resistance is the main cause of cancer recurrence and treatment failure. Our study aimed to investigate the mechanisms by which upregulation of estrogen-related receptor α (ERRα) induced chemoresistance in breast cancer. Methods: Immunohistochemistry (IHC) was used to determine the expression of ERRα in breast cancer and adjacent tissues. Functional analyses (in vitro and in vivo) were performed to confirm the role of ERRα in cancerogenesis and cisplatin chemoresistance in breast cancer. RNA-sequencing, ChIP and dual luciferaseassays were performed to identify the mechanisms by which ERRα promotes chemoresistance in breast cancer. Results: Analyses of ERRα expression among a case-control cohort of 63 annotated tumor specimens demonstrated that ERRα expression was highly expressed in breast cancer tissues. Overexpression of ERRα promoted cell proliferation and metastasis of breast cancer in vitro and in vivo, increased chemoresistant of cisplatin and enhanced the pluripotency; while ERRα knockdown resulted in the opposite effects. We show that ERRα can directly induce CCNE2 expression through binding its promoter region then enhanced the pluripotency of cancer cells and facilitated chemoresistance Overexpression of CCNE2 could reverse the sensitivity of breast cancer cells to cisplatin caused by ERRα depletion, thus resulting in accelerated tumor growth. Conclusions: Our study demonstrates that ERRα acts as oncogene in breast cancer and promotes cisplatin resistance by regulating the transcription of CCNE2 and may serve as a therapeutic target in breast cancer.

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“…ABCC4 is widely expressed in various tissues [50][51][52], and can actively transport a series of organic anions to extracellular, so most of the functional studies on ABCC4 are focused on its effect on cancer chemotherapy [53]. A large number of studies have found that ABCC4 is related to drug resistance in prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, lung cancer and other cancers [54][55][56]. Nonetheless, other studies have uncovered that low expression of ABCC4 can lead to the accumulation of cAMP in cells, which increases the invasiveness and migration of cancer cells [57].…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of a prognostic model of metabolism-related genes driven by somatic mutation in bladder cancer

Liang

Han

et al. 2022

Preprint

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Background Bladder cancer (BLCA) is a highly malignant disease in the urinary system. Somatic mutation is a key feature in cancer occurrence, development, and treatment. Moreover, altered metabolism contributes to patient prognosis. However, the role of metabolism-related genes (MRGs) driven by somatic mutations in BLCA remains unclear. Methods The data were gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The differentially expressed metabolism-related genes (DEMRGs) between normal and BLCA patients were first identified and the functions were discussed. Then The risk model was construct by the DEMRGs with mutation frequency. The accuracy of the risk model was verified by risk curves, Kaplan-Meier (K-M) curves, and Receiver Operating Characteristic (ROC) curves. Subsequently, the correlation of risk score and clinical traits was also researched. Gene Set Enrichment Analysis (GSEA), immune checkpoints, immune microenvironment, and chemotherapeutic drug sensitivity were performed in high- and low-risk groups. And the scRNA-seq revealed that the expression pattern of prognostic biomarkers and cellular heterogeneity. Eventually, the mRNA expression levels of biomarkers were validated by quantitative real-time PCR (qRT-PCR). Results A total of 201 DEMRGs were retrieved, and the DEMRGs were significantly enriched in alcohol metabolic process, cellular modified amino acid metabolic process, and purine metabolism. Then the 24 DEMRGs of the mutation frequency greater than 3% were further analyzed, and a risk model was constructed by 5 biomarkers (FASN, ABCC4, ATP2B4, ATP8B2, and MTHFD1L). Moreover, the AUCs were all greater than 0.6, indicating the risk model had good efficacy. Meanwhile, the riskScore, T-pathologic, age, and N-pathologic were regarded as independent prognostic indicators. The DEMRGs were enriched in OXIDATIVE_PHOSPHORYLATION. Three immune checkpoints, four types of immune cells, and 146 drugs were substantially different in the two risk groups. And the scRNA-seq further disclosed relationships between genes regulation and tracked the development trajectories of distinct cell lineages. Finally, qRT-PCR results showed the expression levels of FASN and MTHFD1L were significantly higher in carcinoma tissue. Conclusion In brief, this study constructed a novel biomarkers, which could improve the prediction of independent prognosis indicators and guide individualized treatment of BLCA patients.

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Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer

Cited by 15 publications

References 66 publications

Nuclear orphan receptor ERRα promotes cisplatin resistance in breast cancer cells by targeting CCNE2

Nuclear orphan receptor ERRα promotes cisplatin resistance in breast cancer cells by targeting CCNE2

ERRα confers oncogenesis and cisplatin resistance via transcriptionally activating CCNE2 in breast cancer

Construction and validation of a prognostic model of metabolism-related genes driven by somatic mutation in bladder cancer

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