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

Author:

Zhang Peng,Wan Yi,Ma Jinrong,Gong Jin,Zhong Ziwei,Cui Yuxin,Zhang Hongli,Da Yanyan,Ma Junpeng,Li Chenxi,Liu Lijuan,Gong Tian,Tan Youwen,Zhang Chengsheng

Abstract

AbstractLactate 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.

Funder

The National Natural Science Foundation of China

The Natural Science Foundation of Jiangxi Province, China

The start-up fund from the First Affiliated Hospital of Nanchang University

Publisher

Springer Science and Business Media LLC

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