HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma

Huang, Jiajun; Zhao, Xiaoyu; Li, Xiang; Peng, Jiwei; Yang, Wen-Lin; Mi, Shengli

doi:10.1371/journal.pbio.3001197

Cited by 23 publications

(19 citation statements)

References 63 publications

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“…We found that eHsp90a interacts with PKM2 and is involved in ePKM2-promoted tumor progression. Similarly, previous mass spectrometry results also demonstrated that PKM2 was an interacting protein of eHsp90a in MCF-7 (39) et al reported that HMGCR increases the activity of glycolysis by upregulation of Hsp90 expression, thus maintaining the levels of PKM2 (40). In this study, we first identified the interaction between Hsp90a and PKM2 in the extracellular environment.…”

Section: Discussionsupporting

confidence: 74%

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Extracellular Hsp90α Supports the ePKM2-GRP78-AKT Axis to Promote Tumor Metastasis

Zhang

Wang

et al. 2022

Front. Oncol.

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Tumor-secreted proteins can provide numerous molecular targets for cancer diagnosis and treatment. Of note, pyruvate kinase M2 (PKM2) is secreted by tumor cells to promote malignant progression, while its regulatory mechanism or the interacting network remains uncovered. In the present study, we identified extracellular heat shock protein 90 alpha (eHsp90α) as one potential interacting protein of ePKM2 by mass spectrometry (MS), which was further verified by pull-down and co-immunoprecipitation analysis. Later, we found that eHsp90α enhanced the effect of ePKM2 on migration and invasion of lung cancer cells. Blocking of Hsp90α activity, on the other hand, attenuated tumor migration or invasion induced by ePKM2. Eventually, the in vivo role of Hsp90α in regulating ePKM2 activity was validated by the mouse xenograft tumor model. Mechanistically, we found that eHsp90α binds to and stabilizes ePKM2 to protect it from degradation in the extracellular environment. Besides, eHsp90α promoted the interaction of ePKM2 with cell surface receptor GRP78, which leads to the activation of the ePKM2/GRP78/AKT axis. Collectively, we unraveled the novel molecular mechanism of eHsp90α in regulating ePKM2 activity during tumor progression, which is beneficial for the development of new treatments against lung cancer.

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Section: Discussionsupporting

confidence: 74%

“…Huang et al. reported that HMGCR increases the activity of glycolysis by upregulation of Hsp90 expression, thus maintaining the levels of PKM2 ( 40 ). In this study, we first identified the interaction between Hsp90α and PKM2 in the extracellular environment.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Hsp90α Supports the ePKM2-GRP78-AKT Axis to Promote Tumor Metastasis

Zhang

Wang

et al. 2022

Front. Oncol.

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“…CRYAB has been reported to be a potential therapeutic target for nasopharyngeal carcinoma (29). The inhibition of HMGCR stabilizes the glycolytic enzyme PKM2 and promotes the growth of RCC (30). MT1G is reported to be hypermethylated in RCC (31).…”

Section: Discussionmentioning

confidence: 99%

A New Prognostic Risk Signature of Eight Ferroptosis-Related Genes in the Clear Cell Renal Cell Carcinoma

et al. 2021

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Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma and has poor prognosis in the locally advanced stage. Ferroptosis, a relatively new type of cell death, has gained significant attention in recent years. This study aimed to explore the prognostic value of ferroptosis-related genes (FRGs) in ccRCC. In this study, 50 differentially expressed FRGs between ccRCC and adjacent normal kidney tissues were identified, 26 of them correlated with overall survival (OS) (P <0.05). Eight optimal FRGs were selected by Lasso regression and multivariate Cox regression analysis, and used to construct a new prognostic risk signature to predict the prognosis of ccRCC patients. In addition, the signature passed the validation of prognostic survival analyses by a significant margin, and the risk score was identified as an independent prognostic marker via Cox regression analyses. Further studies indicated that the signature was significantly correlated with immune cell infiltration. Moreover, the levels of eight FRGs were examined in ccRCC. Collectively, the 8-FRG prognostic risk signature helps the clinicians predict the prognosis and OS of the patients, and standardize prognostic assessments.

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“…DEGs during BMSC osteogenic differentiation are enriched in GO terms and KEGG pathways including ATP binding, metabolic pathways, and fatty acid metabolism. Huang et al identified that the inhibition of HMGCR increased glycolysis, and observed the alteration in HMGCR gene expression during osteoclast differentiation (Huang et al, 2021). HMGCR activity is a key factor in cholesterol biosynthesis and bone formation in rodents (Mundy et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Dynamic transcriptome changes during osteogenic differentiation of bone marrow-derived mesenchymal stem cells isolated from chicken

Wang

Zhai

et al. 2022

Front. Cell Dev. Biol.

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Osteoblasts are indispensable for skeletal growth and maintenance. Bone marrow-derived mesenchymal stem cells (BMSCs) are useful in studying osteogenesis. In this study, BMSCs isolated from White Leghorns were differentiated into osteoblasts in vitro. Cells induced for -1, 0, 1, 11, and 22 d were used for transcriptomic analyses using the HISAT2-Stringtie-DESeq2 pipeline. Weighted correlation network analysis was processed to investigate significant modules, including differentially expressed genes (DEGs), correlated with osteogenic differentiation. Gene ontology and pathway enrichment analyses of DEGs were performed to elucidate the mechanisms of osteoblast differentiation. A total of 534, 1,144, 1,077, and 337 DEGs were identified between cells induced for -1 and 0, 0 and 1, 1 and 11, and 11 and 22 d, respectively (|log2FC| > 1.0, FDR <0.05). DEGs were mainly enriched in pathways related to cell proliferation in the early stage of osteogenic differentiation and pathways, such as the TGF-β signaling pathway, in the middle and late stages of osteogenic differentiation. A protein–protein interaction network of the 87 DEGs in the MEturquoise module within top 5-%-degree value was built utilizing the STRING database. This study is the first to elucidate the transcriptomic changes in the osteogenic differentiation of BMSCs isolated from White Leghorns at different times. Our results provide insight into the dynamic transcriptome changes during BMSC differentiation into osteoblasts in chicken.

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HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma

Cited by 23 publications

References 63 publications

Extracellular Hsp90α Supports the ePKM2-GRP78-AKT Axis to Promote Tumor Metastasis

Extracellular Hsp90α Supports the ePKM2-GRP78-AKT Axis to Promote Tumor Metastasis

A New Prognostic Risk Signature of Eight Ferroptosis-Related Genes in the Clear Cell Renal Cell Carcinoma

Dynamic transcriptome changes during osteogenic differentiation of bone marrow-derived mesenchymal stem cells isolated from chicken

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