HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness

Bi, Lei; Ren, Yidan; Feng, Maoxiao; Meng, Peng; Wang, Qin; Chen, Weiping; Jiao, Qinlian; Wang, Yuli; Li, Du; Zhou, Fuqiong; Jiang, Yucui; Chen, Feiyan; Wang, Chuanxin; Tang, Bo; Wang, Yunshan

doi:10.1158/0008-5472.can-20-3044

Cited by 90 publications

(49 citation statements)

References 60 publications

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“…Liver kinase B1 (also known as STK11) is a tumor suppressor gene that is inactivated in many malignant tumors (Zhang et al, 2021). LKB1 has recently gained significant attention in delineating the complex mechanisms underlying malignant processes such as cell motility, liposome function, protein translation, and various signal transduction pathways (Ciccarese et al, 2019;Bi et al, 2021). However, it is still unclear which of them is related to ESCC tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Protein Arginine Methyltransferase 5 Promotes Esophageal Squamous Cell Carcinoma Proliferation and Metastasis via LKB1/AMPK/mTOR Signaling Pathway

Chen

Zhang

et al. 2021

Front. Bioeng. Biotechnol.

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Background: Esophageal squamous cell carcinoma (ESCC) is the eighth most common cancer in the world. Protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes symmetric and asymmetric methylation on arginine residues of histone and non-histone proteins, is overexpressed in many cancers. However, whether or not PRMT5 participates in the regulation of ESCC remains largely unclear.Methods: PRMT5 mRNA and protein expression in ESCC tissues and cell lines were examined by RT-PCR, western blotting, and immunohistochemistry assays. Cell proliferation was examined by RT-PCR, western blotting, immunohistochemistry assays, MTT, and EdU assays. Cell apoptosis and cell cycle were examined by RT-PCR, western blotting, immunohistochemistry assays, and flow cytometry. Cell migration and invasion were examined by RT-PCR, western blotting, immunohistochemistry assays, and wound-healing and transwell assays. Tumor volume, tumors, and mouse weight were measured in different groups. Lung tissues with metastatic foci, the number of nodules, and lung/total weight were measured in different groups.Results: In the present study, the PRMT5 expression level was dramatically upregulated in ESCC clinical tissues as well as ESCC cell lines (ECA109 and KYSE150). Furthermore, knocking down PRMT5 obviously suppressed cell migration, invasion, proliferation, and cell arrest in G1 phase and promoted cell apoptosis in ESCC cells. Meanwhile, downregulating PRMT5 also increased the expression levels of Bax, caspase-3, and caspase-9, while expression levels of Bax-2, MMP-2, MMP-9, and p21 were decreased, which are members of the cyclin-dependent kinase family. Furthermore, knocking down PRMT5 could increase the expression of LKB1 and the phosphorylation (p)-AMPK expression and decrease the p-mTOR level. Additionally, overexpression of LKB1 could reveal anti-tumor effects in ESCC cell lines by inhibiting ESCC cell, migration, invasion, and proliferation and accelerating cell apoptosis. Besides, upregulating LKB1 expression could increase the levels of Bax, caspase-3, and caspase-9 and weaken the levels of Bax-2, MMP-2, and MMP-9. Moreover, knocking down PRMT5 could weaken the tumor growth and lung metastasis in vivo with upregulating the LKB1 expression and the p-AMPK level and downregulating the p-mTOR expression.Conclusion: PRMT5 may act as a tumor-inducing agent in ESCC by modulating LKB1/AMPK/mTOR pathway signaling.

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Section: Introductionmentioning

confidence: 99%

Protein Arginine Methyltransferase 5 Promotes Esophageal Squamous Cell Carcinoma Proliferation and Metastasis via LKB1/AMPK/mTOR Signaling Pathway

Chen

Zhang

et al. 2021

Front. Bioeng. Biotechnol.

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“…Previous studies have shown that HDAC11 plays a role in hematological system tumors (9,(25)(26)(27), and other system tumors (28,29). For example, Bi et al (30) reported that HDAC11 was highly expressed in hepatocellular carcinoma and closely related to disease prognosis, and the main mechanism was that HDAC11 regulated glycolysis according to the LKB1/AMPK signaling pathway. Another study demonstrated that plasma cell development and survival are dependent upon HDAC11, and knockdown or inhibition of HDAC11 induced cell death in multiple myeloma (MM) cell lines, suggesting this enzyme was a promising therapeutic target in MM (31).…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological characteristics and prognostic significance of HDAC11 protein expression in non-small cell lung cancer: a retrospective study

Lu¹,

Ma²,

Huang³

et al. 2022

Transl Lung Cancer Res

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Background: Although the prognosis of non-small cell lung cancer (NSCLC) can be assessed based on pathological type, disease stage and inflammatory indicators, the prognostic scoring model of NSCLC still needs to improve. HDAC11 is associated with poor prognosis of partial tumors, but its prognostic relationship with NSCLC is poorly understood. In this study, the role of HDAC11 in NSCLC was studied to evaluate relationship with disease prognosis and potential therapeutic target. Methods:The clinicopathological and paracancerous tissues of patients with NSCLC primarily diagnosed in Tangdu Hospital from 2009 to 2013 were collected. Follow-up of patients were made every three months and the last follow-up period was December 2018. The expression of HDAC11 was assessed by immunohistochemistry (IHC). Then, weighted gene co-expression network analysis (WGCNA) was used to analyze the relationship between HDAC11 expression and the prognosis of lung adenocarcinoma (LUAD) patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Kaplan-Meier plotter database was used to verify the connection between hub genes and tumor stage and prognosis. We accessed the relationship between HDAC11 expression and clinicopathological features, and impact on the prognosis. Results:The study assessed 326 patients with NSCLC. Compared with adjacent tissues, HDAC11 expression was upregulated (HR =1.503, 95% CI: 1.172 to 1.927, P=0.001). Kaplan-Meier survival analyses showed that HDAC11 expression was closely related to OS of NSCLC patients (P=0.0011). Univariate and multivariate analyses showed that the independent risk factors of OS were clinical stage, HDAC11 expression, and HDAC11 differentiation (all P≤0.001). HDAC11 was significantly associated with prognosis in LUAD.A total of 1,174 differential genes and WGCNA were obtained to construct a co-expression network in LUAD. The GO and KEGG pathway enrichment analyses showed the relevance with staphylococcus aureus infection, NOD-like receptor signaling pathway, and others. The results of LUAD survival analysis showed that HDAC11-related genes NKX2-5 and FABP7 were significantly associated with LUAD prognosis. Conclusions:The high expression of HDAC11 is related to the poor prognosis of LUAD, and it is expected to become a therapeutic target and prognostic evaluation therapy for LUAD in the future.However, the relevant results need to be further studied and verified.

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“…Histone deacetylase 11 (HDAC11) is substantially expressed in liver cancer and is strongly tied to the prognosis of the disease. HDAC11 knockdown promotes histone acetylation in the related promoter region to increase the transcription of LKB1, consequently activating the signaling pathway of AMPK and hindering the glucose glycolytic pathway, which accordingly inhibits cancer stemness and liver cancer progression and increases sensitivity to sorafenib [ 29 ]. The lncRNA SLC2A1-AS1 is able to regulate aerobic glycolysis and development of hepatocellular carcinoma by inhibiting the STAT3/FOXM1/GLUT1 signaling pathway [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNA ZNF674-AS1 Hinders Proliferation and Invasion of Hepatic Carcinoma Cells through the Glycolysis Pathway

Xie

Sun

et al. 2022

Journal of Oncology

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Purpose. Long noncoding RNAs (lncRNAs) play important roles in regulating various functions of cells at the levels of transcription and posttranscription. Extensive investigations have illustrated that lncRNAs are critical in the glucose metabolism of tumor cells, but their mechanisms of action need to be further explored. This study evaluates the role of lncRNA ZNF674-AS1 on the apoptosis and proliferation of human hepatic carcinoma cells in vitro through the glucose metabolism and its related mechanisms. Methods. Real-time quantitative PCR was employed for detecting the level of expressions for lncRNA ZNF674-AS1 in liver cancer tissues (25 cases), paracancerous tissues, and liver cancer cell lines. The lncRNA ZNF674-AS1 high expression cell strain was constructed by the lentiviral overexpression vector. CCK-8, plate colony formation, transwell assay, lactate production, glucose consumption, and ATP levels were used to detect the change of cell proliferation, colony formation, migration, and invasion, as well as glycolytic capability. Western blot was carried out to detect the expression of HK2, PFKL, PKM2, GLUT1, and PKM1, which are the key proteins of glycolysis in cells. Result. The lncRNA ZNF674-AS1 was undesirably expressed in liver cancer cell lines and tissues. Cell function assessments showed that compared with the blank control group (vector), overexpression of lncRNA ZNF674-AS1 could substantially hinder the proliferation, colony formation, migration, and invasion capability of liver cancer cells. Furthermore, overexpression of lncRNA ZNF674-AS1 could inhibit cell glycolysis (inhibit glucose consumption and reduce intracellular lactate and ATP levels) by inhibiting the expression of key proteins (such as PFKL, HK2, PKM2, and GLUT1) in the process of glycolysis. Conclusion. As a tumor repressor gene, lncRNA ZNF674-AS1 inhibits the expression of key proteins in glycolysis to inhibit glycolysis level, thereby inhibiting cell migration and proliferation. Therefore, lncRNA ZNF674-AS1 could be a potent therapeutic target or a novel diagnostic molecule for patients suffering from liver cancer.

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HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness

Cited by 90 publications

References 60 publications

Protein Arginine Methyltransferase 5 Promotes Esophageal Squamous Cell Carcinoma Proliferation and Metastasis via LKB1/AMPK/mTOR Signaling Pathway

Protein Arginine Methyltransferase 5 Promotes Esophageal Squamous Cell Carcinoma Proliferation and Metastasis via LKB1/AMPK/mTOR Signaling Pathway

Clinicopathological characteristics and prognostic significance of HDAC11 protein expression in non-small cell lung cancer: a retrospective study

LncRNA ZNF674-AS1 Hinders Proliferation and Invasion of Hepatic Carcinoma Cells through the Glycolysis Pathway

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