ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption

Li, Xin; Zhang, Kejing; Hu, Yu; Luo, Na

doi:10.1042/bsr20192465

Cited by 20 publications

(17 citation statements)

References 37 publications

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“…Moreover, SHMT2 has been found to be associated with a poor prognosis in hepatocellular carcinoma (Ji et al, 2019), intrahepatic cholangiocarcinoma (Ning et al, 2018), breast cancer (Bernhardt et al, 2017) and gastrointestinal tumors (Liu et al, 2019). In addition, ERRα can activate SHMT2 transcription by targeting its promoter region to enhance breast cancer resistance to lapatinib (Li et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of SHMT2 Predicts a Poor Prognosis and Promotes Tumor Cell Growth in Bladder Cancer

Zhang

Yang

2021

Front. Genet.

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SHMT2 was overexpressed in many tumors, however, the role of SHMT2 in bladder cancer (BLCA) remains unclear. We first analyzed the expression pattern of SHMT2 in BLCA using the TNMplot, Oncomine, the Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) databases. Next, the association between SHMT2 expression and overall survival (OS)/disease-free survival (DFS) in BLCA patients were analyzed using TCGA and PrognoScan database. The correlation between SHMT2 expression and clinicopathology was determined using TCGA database. Furthermore, the genes co-expressed with SHMT2 and their underlying molecular function in BLCA were explored based on the Oncomine database, Metascape and gene set enrichment analysis (GSEA). Finally, the effects of SHMT2 on cell proliferation, cell cycle, and apoptosis were assessed using in vitro experiments. As a results, SHMT2 was significantly overexpressed in BLCA tissues and cells compared to normal bladder tissues and cells. A high SHMT2 expression predicts a poor OS of BLCA patients. In addition, SHMT2 expression was higher in patients with a high tumor grade and in those who were older than 60 years. However, the expression of SHMT2 was not correlated with gender, tumor stage, lymph node stage, and distant metastasis stage. Finally, overexpression of SHMT2 promoted BLCA cell proliferation and suppressed apoptosis, the silencing of SHMT2 significantly inhibited BLCA cell proliferation by impairing the cell cycle, and promoting apoptosis. SHMT2 mediates BLCA cells growth by regulating STAT3 signaling. In summary, SHMT2 regulates the proliferation, cell cycle and apoptosis of BLCA cells, and may act as a candidate therapeutic target for BLCA.

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Section: Discussionmentioning

confidence: 99%

Overexpression of SHMT2 Predicts a Poor Prognosis and Promotes Tumor Cell Growth in Bladder Cancer

Zhang

Yang

2021

Front. Genet.

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“…The involvement of ERRα in drug resistance has been widely studied in breast cancer and osteosarcoma (44)(45)(46)(47)(48). However, its role in PCa drug resistance was rarely examined.…”

Section: Discussionmentioning

confidence: 99%

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

Huang

Shen

et al. 2020

Front. Oncol.

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Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERRα) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERRα was involved in docetaxel resistance in PCa. Overexpression of ERRα conferred docetaxel resistance in PCa cell lines, and cells with ERRα downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERRα manipulation in cells. Moreover, both ERRα and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERRα knockdown. The knockdown of ERRα also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERRα as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERRα and ABCC4 in PCa patients, and a number of potential ERRα/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERRα in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERRα as a potential therapeutic target for drug-resistant PCa.

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“…Moreover, ERRα and PGC-1α regulate the expression of genes involved in the folate cycle (Audet-Walsh et al, 2016) and the methionine cycle (Vernier et al, 2020a). Furthermore, ERRα, ERRγ, and PGC-1α regulate the enzymes involved in glutamine metabolism in HER2-positive breast cancer cells (McGuirk et al, 2013;Deblois et al, 2016;Vernier et al, 2020b), which is implicated in resistance to the HER2 inhibitor lapatinib (Li et al, 2020;Vernier et al, 2020b). A recent study showed that ERRα and ERRγ modulate ROS homeostasis, and that ERRγ is associated with resistance to paclitaxel, an anticancer drug that induces ROS.…”

Section: Err/pgc-1-mediated Metabolic Reprogramming In Breast Cancermentioning

confidence: 99%

Emerging Roles of COX7RP and Mitochondrial Oxidative Phosphorylation in Breast Cancer

Kamada

Takeiwa

Ikeda

et al. 2022

Front. Cell Dev. Biol.

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Metabolic alterations are critical events in cancers, which often contribute to tumor pathophysiology. While aerobic glycolysis is a known characteristic of cancer-related metabolism, recent studies have shed light on mitochondria-related metabolic pathways in cancer biology, including oxidative phosphorylation (OXPHOS), amino acid and lipid metabolism, nucleic acid metabolism, and redox regulation. Breast cancer is the most common cancer in women; thus, elucidation of breast cancer-related metabolic alteration will help to develop cancer drugs for many patients. We here aim to define the contribution of mitochondrial metabolism to breast cancer biology. The relevance of OXPHOS in breast cancer has been recently defined by the discovery of COX7RP, which promotes mitochondrial respiratory supercomplex assembly and glutamine metabolism: the latter is also shown to promote nucleic acid and fatty acid biosynthesis as well as ROS defense regulation. In this context, the estrogen-related receptor (ERR) family nuclear receptors and collaborating coactivators peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) are essential transcriptional regulators for both energy production and cancer-related metabolism. Summarizing recent findings of mitochondrial metabolism in breast cancer, this review will aim to provide a clue for the development of alternative clinical management by modulating the activities of responsible molecules involved in disease-specific metabolic alterations.

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ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption

Cited by 20 publications

References 37 publications

Overexpression of SHMT2 Predicts a Poor Prognosis and Promotes Tumor Cell Growth in Bladder Cancer

Overexpression of SHMT2 Predicts a Poor Prognosis and Promotes Tumor Cell Growth in Bladder Cancer

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

Emerging Roles of COX7RP and Mitochondrial Oxidative Phosphorylation in Breast Cancer

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