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Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment.

ABSTRACT: Lactate dehydrogenase B (LDHB) reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate and expressed in various malignancies. However, the role of LDHB in modulating immune responses against hepatocellular carcinoma (HCC) remains largely unknown. Here, we found that down-regulation of lactate dehydrogenase B (LDHB) was coupled with the promoter hypermethylation and knocking down the DNA methyltransferase 3A (DNMT 3A) restored LDHB expression levels in HCC cell lines. Bioinformatics analysis of the HCC cohort from The Cancer Genome Atlas revealed a significant positive correlation between LDHB expression and immune regulatory signaling pathways and immune cell infiltrations. Moreover, immune checkpoint inhibitors (ICIs) have shown considerable promise for HCC treatment and patients with higher LDHB expression responded better to ICIs. Finally, we found that overexpression of LDHB suppressed HCC growth in immunocompetent but not in immunodeficient mice, suggesting that the host immune system was involved in the LDHB-medicated tumor suppression. Our findings indicate that DNMT3A-mediated epigenetic silencing of LDHB may contribute to HCC progression through remodeling the tumor immune microenvironment, and LDHB may become a potential prognostic biomarker and therapeutic target for HCC immunotherapy.

SUBMITTER: Zhang P

PROVIDER: S-EPMC11091036 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment.

Zhang Peng P Wan Yi Y Ma Jinrong J Gong Jin J Zhong Ziwei Z Cui Yuxin Y Zhang Hongli H Da Yanyan Y Ma Junpeng J Li Chenxi C Liu Lijuan L Gong Tian T Tan Youwen Y Zhang Chengsheng C

Cancer immunology, immunotherapy : CII 20240513 7

Lactate dehydrogenase B (LDHB) reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate and expressed in various malignancies. However, the role of LDHB in modulating immune responses against hepatocellular carcinoma (HCC) remains largely unknown. Here, we found that down-regulation of lactate dehydrogenase B (LDHB) was coupled with the promoter hypermethylation and knocking down the DNA methyltransferase 3A (DNMT 3A) restored LDHB expression levels in HCC cell lines. Bi ...[more]

PMID: 38739169

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Project description:BackgroundEpigenetics regulate gene expression without altering the DNA sequence. Epigenetics targeted chemotherapeutic approach can be used to overcome treatment resistance and low response rate in HCC. However, a comprehensive review of genomic data was carried out to determine the role of epigenesis in the tumor microenvironment (TME), immune cell-infiltration characteristics in HCC is still insufficient.MethodsThe association between epigenetic-related genes (ERGs), inflammatory response-related genes (IRRGs) and CRISPR genes was determined by merging genomic and CRISPR data. Further, characteristics of immune-cell infiltration in the tumor microenvironment was evaluated.ResultsNine differentially expressed genes (ANP32B, ASF1A, BCORL1, BMI1, BUB1, CBX2, CBX3, CDK1, and CDK5) were shown to be independent prognostic factors based on lasso regression in the TCGA-LIHC and ICGC databases. In addition, the results showed significant differences in expression of PDCD-1 (PD-1) and CTLA4 between the high- and low-epigenetic score groups. The CTRP and PRISM-derived drug response data yielded four CTRP-derived compounds (SB-743921, GSK461364, gemcitabine, and paclitaxel) and two PRISM-derived compounds (dolastatin-10 and LY2606368). Patients with high ERGs benefited more from immune checkpoint inhibitor (ICI) therapy than patients with low ERGs. In addition, the high ERGs subgroup had a higher T cell exclusion score, while the low ERGs subgroup had a higher T cell dysfunction. However, there was no difference in microsatellite instability (MSI) score among the two subgroups. Further, genome-wide CRISPR-based loss-of function screening derived from DepMap was conducted to determine key genes leading to HCC development and progression. In total, 640 genes were identified to be essential for survival in HCC cell lines. The protein-protein interaction (PPI) network demonstrated that IRRGs PSEN1 was linked to most ERGs and CRISPR genes such as CDK1, TOP2A, CBX2 and CBX3.ConclusionEpigenetic alterations of cancer-related genes in the tumor microenvironment play a major role in carcinogenesis. This study showed that epigenetic-related novel biomarkers could be useful in predicting prognosis, clinical diagnosis, and management in HCC.

Project description:BackgroundThe role of TMEM176A in human hepatocellular carcinoma (HCC) is unknown. This study explored the epigenetic regulation and function of TMEM176A in human HCC.Materials and methodsTwelve HCC cell lines and 126 cases of primary cancer were analyzed. Methylation-specific PCR, immunohistochemistry, flow cytometry, and xenograft mouse models were employed.ResultsTMEM176A was highly expressed in SNU387, SNU182, Huh1, and SNU475 cells; reduced expression was observed in HepG2 and PLC/PRF/5 cells; and no expression was found in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells. Unmethylation of the TMEM176A promoter was detected in SNU387, SNU182, Huh1, and SNU475 cells; partial methylation was observed in HepG2 and PLC/PRF/5 cells; and complete methylation was found in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells. Upon treatment with 5-Aza-2-deoxycytidine, re-expression of TMEM176A was detected in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells; increased expression of TMEM176A was observed in HepG2 and PLC/PRF/5 cells; and no expression changes were found in SNU387, SNU182, Huh1, and SNU475 cells. The TMEM176A promoter region was methylated in 75.4% (95/126) of primary human HCC. Reduced expression of TMEM176A was associated with promoter region methylation (P < 0.05). No association was found between TMEM176A promoter methylation and age, gender, HBV infection, liver cirrhosis, tumor size, lymph node metastasis, vessel cancerous embolus, number of lesions, and TNM stage (all P > 0.05). These results demonstrated that the expression of TMEM176A is regulated by promoter region methylation. Methylation of the TMEM176A promoter was significantly associated with tumor cell differentiation (P < 0.05) and was an independent prognostic factor for poor 3-year overall survival (OS, P < 0.05). TMEM176A expression induced cell apoptosis; inhibited cell proliferation, migration, and invasion; suppressed human HCC cell xenograft growth in mice; and inhibited ERK signaling in HCC cells.ConclusionThe promoter region of TMEM176A is frequently methylated in human HCC, and the expression of TMEM176A is regulated by promoter region methylation. Methylation of the TMEM176A promoter may serve as a diagnostic and prognostic marker in HCC. TMEM176A suppresses HCC growth by inhibiting the ERK signaling pathway.

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Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment.

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Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment.

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