LDHB Mediates Histone Lactylation to Activate PD-L1 and Promote Ovarian Cancer Immune Escape.

IF 1.8 4区医学 Q3 ONCOLOGY

Cancer Investigation Pub Date : 2024-11-25 DOI:10.1080/07357907.2024.2430283

Xuemei Hu, Zhenqiang Huang, Lingyun Li

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引用次数: 0

Abstract

Background: To investigate the effects of LDHB on lactylation of programmed cell death 1 ligand (PD-L1) and immune evasion of ovarian cancer.

Methods: Ovarian cancer cells were transfected with LDHB siRNA and cultured with primed T cells. Cell proliferation and viability were measured by cell counting kit 8 (CCK-8) and colony formation assay. The production of immune factors was detected by enzyme-linked immunosorbent assay (ELISA). The histone lactylation and activity of PD-L1 promoter were measured by chromatin immunoprecipitation (ChIP)-qPCR assay and luciferase reporter gene assay, respectively.

Results: Knockdown of LDHB notably inhibited the growth, glucose uptake, lactate production, and ATP production of ovarian cancer cells. Knockdown of LDHB enhanced the killing effects of T cells, led to increased production of immune activation factors IL-2, TNF-α, and IFN-γ, as well as elevated the levels of granzyme B and perforin. Mechanical study identified that LDHB regulated the H3K18 lactylation (H3K18la) modification on PD-L1 promoter region to promote its expression. Overexpression of PD-L1 abolished the immune activation effects that induced by siLDHB.

Conclusion: The LDHB modulated lactate production and the histone lactylation on PD-L1 promoter, which ultimately regulated its expression and participated in the immune evasion of ovarian cancer cells.

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LDHB 介导组蛋白乳化，激活 PD-L1 并促进卵巢癌免疫逃逸。

背景：研究LDHB对程序性细胞死亡1配体（PD-L1）乳化和卵巢癌免疫逃避的影响：研究 LDHB 对卵巢癌程序性细胞死亡 1 配体（PD-L1）乳化及免疫逃避的影响：方法：用LDHB siRNA转染卵巢癌细胞并与引物T细胞一起培养。用细胞计数试剂盒 8（CCK-8）和集落形成试验检测细胞的增殖和活力。用酶联免疫吸附试验（ELISA）检测免疫因子的产生。染色质免疫沉淀（ChIP）-qPCR测定和荧光素酶报告基因测定分别检测了组蛋白乳化和PD-L1启动子的活性：结果：LDHB的敲除显著抑制了卵巢癌细胞的生长、葡萄糖摄取、乳酸生成和ATP生成。LDHB的敲除增强了T细胞的杀伤作用，导致免疫激活因子IL-2、TNF-α和IFN-γ的产生增加，并提高了颗粒酶B和穿孔素的水平。机械研究发现，LDHB能调节PD-L1启动子区的H3K18乳化（H3K18la）修饰，从而促进其表达。过量表达PD-L1可消除siLDHB诱导的免疫激活效应：结论：LDHB可调节乳酸的产生和PD-L1启动子上组蛋白的乳化，最终调控PD-L1的表达，参与卵巢癌细胞的免疫逃避。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Investigation 医学-肿瘤学

CiteScore

3.80

自引率

4.20%

发文量

审稿时长

8.5 months

期刊介绍： Cancer Investigation is one of the most highly regarded and recognized journals in the field of basic and clinical oncology. It is designed to give physicians a comprehensive resource on the current state of progress in the cancer field as well as a broad background of reliable information necessary for effective decision making. In addition to presenting original papers of fundamental significance, it also publishes reviews, essays, specialized presentations of controversies, considerations of new technologies and their applications to specific laboratory problems, discussions of public issues, miniseries on major topics, new and experimental drugs and therapies, and an innovative letters to the editor section. One of the unique features of the journal is its departmentalized editorial sections reporting on more than 30 subject categories covering the broad spectrum of specialized areas that together comprise the field of oncology. Edited by leading physicians and research scientists, these sections make Cancer Investigation the prime resource for clinicians seeking to make sense of the sometimes-overwhelming amount of information available throughout the field. In addition to its peer-reviewed clinical research, the journal also features translational studies that bridge the gap between the laboratory and the clinic.