MiR-933 accelerates the growth of liver cancer cells by enhancing pyruvate kinase isoform M2.
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ABSTRACT:
SUBMITTER: Wang L
PROVIDER: S-EPMC10909591 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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miR-933 accelerates the growth of liver cancer cells by enhancing pyruvate kinase isoform M2.
Wang Liyan L Li Shujie S Liu Xinlei X Xie Sijie S Song Shuting S Jiang Xiaoxue X Lu Dongdong D
Genes & diseases 20231130 4
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Project description:Many cancer cells have increased rates of aerobic glycolysis, a phenomenon termed the Warburg effect. In addition, in tumors there is a predominance of expression of the M2 isoform of pyruvate kinase (PKM2). M2 expression was previously shown to be necessary for aerobic glycolysis and to provide a growth advantage to tumors. We report that knockdown of pyruvate kinase in tumor cells leads to a decrease in the levels of pyruvate kinase activity and an increase in the pyruvate kinase substrate phosphoenolpyruvate. However, lactate production from glucose, although reduced, was not fully inhibited. Furthermore, we are unique in reporting increased serine and glycine biosynthesis from both glucose and glutamine following pyruvate kinase knockdown. Although pyruvate kinase knockdown results in modest impairment of proliferation in vitro, in vivo growth of established xenograft tumors is unaffected by PKM2 absence. Our findings indicate that PKM2 is dispensable for tumor maintenance and growth in vivo, suggesting that other metabolic pathways bypass its function.
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Project description:Energy metabolism programming is a hallmark of cancer, and serves as a potent target of cancer therapy. Valproic acid (VPA), a broad Class I histone deacetylases (HDACs) inhibitor, has been used as a therapeutic agent for cancer. However, the detail mechanism about the potential role of VPA on the Warburg effect in breast cancer remains unclear. In this study, we highlight that VPA significantly attenuates the Warburg effect by decreasing the expression of pyruvate kinase M2 isoform (PKM2), leading to inhibited cell proliferation and reduced colony formation in breast cancer MCF-7 and MDA-MB-231 cells. Mechanistically, Warburg effect suppression triggered by VPA was mediated by inactivation of ERK1/2 phosphorylation through reduced HDAC1 expression, resulting in suppressing breast cancer growth. In summary, we uncover a novel mechanism of VPA in regulating the Warburg effect which is essential for developing the effective approach in breast cancer therapy.
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Project description:Muscle type of pyruvate kinase (PKM) is one of the key mediators of the Warburg effect and tumor metabolism. Due to alternative splicing, there are at least 12 known isoforms of the PKM gene, of which PKM1 and PKM2 are two major isoforms with only a 23 amino acid sequenced difference but quite different characteristics and functions. It was previously thought the isoform switch from PKM1 to PKM2 resulted in high PKM2 expression in tumors, providing a great advantage to tumor cells. However, this traditional view was challenged by two recent studies; one study claimed that this isoform switch does not occur during the Warburg effect; the other study asserted that the isoform switch is tissue-specific. Here, we re-analyzed the RNA sequencing data of 25 types of human tumors from The Cancer Genome Atlas Data Portal, and confirmed that PKM2 was the major isoform in the tumors and was highly elevated in addition to the entire PKM gene. We further demonstrated that the expression level of PKM1 significantly declined even though there was substantially increased expression of the entire PKM gene. The proportion of PKM1 in total transcript variants also significantly declined in tumors but the proportion of PKM2 did not change accordingly. Therefore, we conclude that the isoform switch of PKM1 does indeed occur, but it switches to other isoforms rather than PKM2. Considering the change in the expression levels of PKM1, PKM2 and the entire PKM gene, we propose that the upregulation of PKM2 is primarily due to elevated transcriptional levels of the entire PKM gene, instead of the isoform switch.
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Project description:Researches indicate miR-3200 is closely related to tumorigenesis, However, the role of miR-3200 in human hepatocarcinogenesis is still unclear. In this study, we clearly demonstrate that miR-3200 accelerates the growth of liver cancer cells in vivo and in vitro. Obviously, these findings are noteworthy that miR-3200 affects the transcriptional regulation for several genes, including DSP，BABAM2, Rab7A,SQSTM1,PRKAG2,CDK1,ABCE1,BECN1,PTEN,UPRT. And miR-3200 affects the transcriptional ability of several genes, such as, upregulating CADPS, DSP,FBXO32, PPCA,SGK1, PATXN7L1, PLK2,ITGB5,FZD3,HOXC8,HSPA1A,C-Myc,CyclnD1,CyclinE,PCNA and down -regulating SUV39H1, MYO1G, OLFML3, CBX5, PPDE2A, HOXA7, RAD54L, CDC45,SHMT7,MAD2L1,P27,IQGAP3,PTEN,P57,SCAMP3,etc...On the other hand, it is obvious that miR-3200 affects the translational ability of several genes, such as, upregulating GNS,UPRT,EIFAD,YOS1,SGK1,K-Ras,PKM2,C-myc,Pim1,CyclinD1,mTOR,erbB-2,CyclinE,PCNA,RRAS,ARAF,RAPH1,etc.. and down-regulating KDM2A, AATF, TMM17B, RAB8B, MYO1G,P21WAF1/Cip1,GADD45,PTEN,P27,P18,P57,SERBP1,RPL34,UFD1,Bax,ANXA6,GSK3β. Strikingly, miR-3200 affects some signaling pathway in liver cancer, including carbon metabolism signaling pathway, DNA replication pathway, FoxO signaling pathway, Hippo signaling pathway, serine and threonine metabolism signaling pathway, mTOR signaling pathway, Fatty acid biosynthesis signaling pathway, carcinogenesis-receptor activation signaling pathway, autophagy signaling pathway. Furthermore, our results suggest that miR-3200 enhances expression of RAB7A, and then Rab7A regulates the carcinogenic function of miR-3200 by increasing telomere remodeling in human liver cancer. These results are of great significance for the prevention and treatment of human liver cancer.
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Project description:Most tumor cells take up more glucose than normal cells but metabolize glucose via glycolysis even in the presence of normal levels of oxygen, a phenomenon known as the Warburg effect. Tumor cells commonly express the embryonic M2 isoform of pyruvate kinase (PKM2) that may contribute to the metabolism shift from oxidative phosphorylation to aerobic glycolysis and tumorigenesis. Here we show that PKM2 is acetylated on lysine 305 and that this acetylation is stimulated by high glucose concentration. PKM2 K305 acetylation decreases PKM2 enzyme activity and promotes its lysosomal-dependent degradation via chaperone-mediated autophagy (CMA). Acetylation increases PKM2 interaction with HSC70, a chaperone for CMA, and association with lysosomes. Ectopic expression of an acetylation mimetic K305Q mutant accumulates glycolytic intermediates and promotes cell proliferation and tumor growth. These results reveal an acetylation regulation of pyruvate kinase and the link between lysine acetylation and CMA.
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Project description:The main therapeutic goal for diabetic retinopathy (DR) is to prevent vision loss in patients with diabetes mellitus. Identifying the visual complications at a preclinical juncture will offer an early therapeutic window for diagnosis and intervention. Very recently, we found that pyruvate kinase M2 isoform (PKM2) regulates visual function through regulation of a key enzyme, phosphodiesterase 6β (Pde6β), involved in modulating photoreceptor functions. A recent study showed that the activation of PKM2 protects mitochondrial integrity in diabetic nephropathy. In the present study, we examined the role of PKM2 in DR in a mouse model that has both phenotypes of obesity and type II diabetes. In DR, we found decreased expression of PKM2 and Pde6β expression, but not PKM1. Consistent with decreased Pde6β expression, the db/db mice had reduced rod photoreceptor function. We found increased pyruvate kinase activity and a decreased ratio of reduced/oxidized redox in db/db mouse retina compared with control retinas. There was no significant difference in the levels of lactate between db/db and control mouse retina. Our findings suggest that reduced expression of PKM2 with unchanged PKM1 expression might be responsible for higher pyruvate kinase activity in db/db mouse retina. Our studies suggest that PKM2 has a role in DR. The results support that PKM2 may serve as a therapeutic target in the treatment of DR.
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Project description:Hepatocellular carcinoma (HCC) is an aggressive tumor, with a high mortality rate due to late symptom presentation and frequent tumor recurrences and metastasis. It is also a rapidly growing tumor supported by different metabolic mechanisms; nevertheless, the biological and molecular mechanisms involved in the metabolic reprogramming in HCC are unclear. In this study, we found that pyruvate kinase M2 (PKM2) was frequently over-expressed in human HCCs and its over-expression was associated with aggressive clinicopathological features and poor prognosis of HCC patients. Furthermore, knockdown of PKM2 suppressed aerobic glycolysis and cell proliferation in HCC cell lines in vitro. Importantly, knockdown of PKM2 hampered HCC growth in both subcutaneous injection and orthotopic liver implantation models, and reduced lung metastasis in vivo. Of significance, PKM2 over-expression in human HCCs was associated with a down-regulation of a liver-specific microRNA, miR-122. We further showed that miR-122 interacted with the 3UTR of the PKM2 gene. Re-expression of miR-122 in HCC cell lines reduced PKM2 expression, decreased glucose uptake in vitro, and suppressed HCC tumor growth in vivo. Our clinical data and functional studies have revealed a novel biological mechanism involved in HCC metabolic reprogramming.
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Project description:Cutaneous wound healing is a complex and dynamic process with high energy demand. The activation of glycolysis is essential for restoring the structure and function of injured tissues in wounds. Pyruvate kinase M2 (PKM2) is an enzyme that plays a crucial role in the last step of glycolysis. PKM2-mediated glycolysis is known to play an important role in diseases related to regeneration and inflammation. However, the role of PKM2 in wound healing has not been fully elucidated. In this study, we found that PKM2 expression and pyruvate kinase (PK) activity were increased with the activation of Wnt/β-catenin signaling during wound healing in mice. TEPP-46, an allosteric activator of PKM2, enhanced HaCaT human keratinocyte migration and cutaneous wound healing with an increment of PK activity. Moreover, we confirmed the effect of co-treatment with TEPP-46 and KY19382, a Wnt/β-catenin signaling activator through the interference with the CXXC-type zinc finger protein 5 (CXXC5) Dishevelled interaction, on wound healing. The combination treatment significantly accelerated wound healing, which was confirmed by the expression level of PCNA, keratin 14, and α-SMA. Furthermore, co-treatment induced angiogenesis in the wound beds. Overall, activation of both glycolysis and Wnt/β-catenin signaling has the potential to be used as a therapeutic approach for wound healing.
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Project description:Cancer cells are known to adopt aerobic glycolysis in order to fuel tumor growth, but the molecular basis of this metabolic shift remains largely undefined. O-GlcNAcase (OGA) is an enzyme harboring O-linked β-N-acetylglucosamine (O-GlcNAc) hydrolase and cryptic lysine acetyltransferase activities. Here, we report that OGA is upregulated in a wide range of human cancers and drives aerobic glycolysis and tumor growth by inhibiting pyruvate kinase M2 (PKM2). PKM2 is dynamically O-GlcNAcylated in response to changes in glucose availability. Under high glucose conditions, PKM2 is a target of OGA-associated acetyltransferase activity, which facilitates O-GlcNAcylation of PKM2 by O-GlcNAc transferase (OGT). O-GlcNAcylation inhibits PKM2 catalytic activity and thereby promotes aerobic glycolysis and tumor growth. These studies define a causative role for OGA in tumor progression and reveal PKM2 O-GlcNAcylation as a metabolic rheostat that mediates exquisite control of aerobic glycolysis.
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Project description:The tumor form of pyruvate kinase M2 has been suggested to promote cellular anabolism by redirecting the metabolism to cause accumulation of glycolytic intermediates and increasing flux through the pentose phosphate pathway, which is a metabolic pathway parallel to glycolysis. Both rod and cone photoreceptors express the tumor form of pyruvate kinase M2. Recent studies from our laboratory show that PKM2 is functionally important for rod photoreceptor structure, function, and viability. However, the functional role of PKM2 in cones is not known. In this study, we conditionally deleted PKM2 in cones (cone-cre PKM2-KO) and found that loss of PKM2 results in the upregulation of PKM1 and a significant loss of cone function and cone degeneration in an age-dependent manner. Gene expression studies on cone-cre PKM2-KO show decreased expression of genes regulating glycolysis, PPP shunt, and fatty acid biosynthesis. Consistent with these observations, cones lacking PKM2 have significantly shorter cone outer segments than cones with PKM2. Our studies clearly suggest that PKM2 is essential for the anabolic process in cones to keep them alive for normal functioning and to support cone structure.
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