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LncCCAT1 interaction protein PKM2 up-regulates SREBP2 phosphorylation to promote osteosarcoma tumorigenesis by enhancing the Warburg effect and lipogenesis

ABSTRACT: Pyruvate kinase M2 (PKM2) plays an important role in the consumption of glucose and the production of lactic acid, the striking feature of cancer metabolism. The association of PKM2 with osteosarcoma (OS) has been reported but its role in OS has not. To study this, we obtained PKM2-bound RNAs in HeLa cells. Peak calling analysis revealed that PKM2 binds to long noncoding RNAs (lncRNAs), which are associated with cancer pathogenesis and development. Validation of the PKM2-lncRNA interaction in the human OS cell line showed that lncRNA colon cancer associated transcript-1 (lncRNACCAT1) interacts with PKM2, which upregulates the phosphorylation of sterol regulatory element-binding protein 2. These factors promote the Warburg effect, lipogenesis, and OS cell growth. PKM2 seems to be a key regulator in OS by binding to lncCCAT1. This further extends the biological functions of PKM2 in tumorigenesis and makes it a novel potential therapeutic for OS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184327 | GEO | 2022/03/23

REPOSITORIES: GEO

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MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation

Project description:Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. However, the precise mechanisms are not completely understood. Here we dissect how MNX1-AS1 reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the nucleus. We found that MNX1-AS1 expression was frequently overexpressed in hepatocellular carcinoma (HCC). In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. Upon EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, Glut1 and PDK1) are upregulated. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in vivo, indicative of the significant contribution of MNX1-AS1 to tumorigenesis. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.

2022-11-23 | GSE213064 | GEO

LncCCAT1 interaction protein PKM2 up-regulates SREBP2 phosphorylation to promote osteosarcoma tumorigenesis by enhancing the Warburg effect and lipogenesis

Project description:LncCCAT1 interaction protein PKM2 up-regulates SREBP2 phosphorylation to promote osteosarcoma tumorigenesis by enhancing the Warburg effect and lipogenesis

| PRJNA764080 | ENA

LncCCAT1 interaction protein PKM2 upregulates SREBP2 phosphorylation to promote osteosarcoma tumorigenesis by enhancing the Warburg effect and lipogenesis.

Project description:Pyruvate kinase M2 (PKM2) plays an important role in the consumption of glucose and the production of lactic acid, the striking feature of cancer metabolism. The association of PKM2 with osteosarcoma (OS) has been reported but its role in OS has yet to be elucidated. To study this, PKM2‑bound RNAs in HeLa cells, a type of cancer cells widely used in the study of molecular function and mechanism, were obtained. Peak calling analysis revealed that PKM2 binds to long noncoding RNAs (lncRNAs), which are associated with cancer pathogenesis and development. Validation of the PKM2‑lncRNA interaction in the human OS cell line revealed that lncRNA colon cancer associated transcript‑1 (lncCCAT1) interacted with PKM2, which upregulated the phosphorylation of sterol regulatory element‑binding protein 2 (SREBP2). These factors promoted the Warburg effect, lipogenesis, and OS cell growth. PKM2 appears to be a key regulator in OS by binding to lncCCAT1. This further extends the biological functions of PKM2 in tumorigenesis and makes it a novel potential therapeutic for OS.

| S-EPMC8923656 | biostudies-literature

MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation

Project description:MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation

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Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. RNA was isolated from flash frozen ground whole liver tissue of 35 week old PKM2 KO and WT mice. Three independent mice from each condition were used as biological replicates.

2016-03-25 | E-GEOD-79535 | biostudies-arrayexpress

EGF promotes PKM2 O-GlcNAcylation by stimulating O-GlcNAc transferase phosphorylation at Y976 and their subsequent association

Project description:EGF is one of the most well-characterized growth factors and plays a crucial role in cell proliferation and differentiation. EGFR has been extensively explored as a therapeutic target against multiple types of cancers, such as lung cancer and glioblastoma. Recent studies have established a connection between deregulated EGF signaling and metabolic reprogramming, especially rewiring in aerobic glycolysis, which is also known as the Warburg effect and recognized as a hallmark in cancer. Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme controlling the final step of glycolysis and serves as a major regulator of the Warburg effect. We previously showed that PKM2 T405/S406 O-GlcNAcylation, a critical mark important for PKM2 detetramerization and activity, was markedly upregulated by EGF. However, the mechanism by which EGF regulates PKM2 O-GlcNAcylation still remains uncharacterized. Here we demonstrated that EGF promoted O-GlcNAc transferase (OGT) binding to PKM2 by stimulating OGT Y976 phosphorylation. As a consequence, PKM2 O-GlcNAcylation and detetramerization were upregulated, leading to a significant decrease in PKM2 activity. Moreover, other than PKM2, the association of additional phosphotyrosine binding proteins, including STAT1, STAT3, STAT5, PKCδ and p85, which are reported factors bearing O-GlcNAcylation, with OGT was also enhanced when Y976 was phosphorylated. Together, EGF-dependent Y976 phosphorylation is critical for OGT-PKM2 interaction and we propose that this post-translational modification might be important for the substrate selection by OGT.

2022-08-22 | PXD031593 | Pride

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

2016-03-25 | GSE79535 | GEO

Expression profiling of E14 cells overexpressing Hk2/Pkm2

Project description:Purpose: In this study, we compared transcriptome profiling (RNA-seq) between normal mouse embryonic stem cell (E14) and Hexokinase2 (Hk2)/ Pyruvate Kinase M2 (Pkm2) overexpressed E14 cell. Result: Using an optimized data analysis workflow, we mapped over 4 billion sequence reads per sample to the mouse genome (build mm9) and identified 28698 transcripts in 5 samples. Conclusion: Our study represents the first detailed analysis of Hk2/ Pkm2 overexpressed E14 cell transcriptomes, generated by RNA-seq technology We compared transcriptome profiling (RNA-Seq) between normal mouse embryonic stem cell (E14) and E14 cells over-expressing Hexokinase2 (Hk2)/Pyruvate Kinase M2 (Pkm2)

2016-07-03 | E-GEOD-65246 | biostudies-arrayexpress

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Project description:Analysis of transcriptome post hypoxia treatment in breast cancer cell line and its PKM2 knockout mutant In order to explore the role of PKM2 in influencing global transcriptional alterations under hypoxia in breast cancer, we performed Human Transcriptome Array 2.0 with a breast cancer cell line and its PKM2 knockout mutant cell line.

2023-07-05 | GSE190401 | GEO

Nuclear PKM2 binds pre-mRNA at folded G-quadruplexes and reveals their gene regulatory role

Project description:Nuclear translocation of the key metabolic enzyme Pyruvate Kinase Isoform 2 (PKM2) is widely observed in cancer, but its contribution to gene regulation and pathogenesis remains unclear. Here we find that PKM2 specifically recognized folded RNA G-quadruplex (rG4) structures in vitro with high affinity. In human cells, nuclear PKM2 bound thousands of precursor mRNAs at potential rG4 sites and translocation of PKM2 to the nucleus resulted in increased expression of rG4-containing mRNAs.

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