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SETDB1 诱导的 Warburg 效应通过 c-MYC-LDHA 轴导致的细胞质定位增强了乳腺癌的迁移和侵袭。

Cytoplasmic localization of SETDB1‑induced Warburg effect via c‑MYC‑LDHA axis enhances migration and invasion in breast carcinoma.

机构信息

Department of Pathology, Nantong Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu 226006, P.R. China.

Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China.

出版信息

Int J Mol Med. 2024 Apr;53(4). doi: 10.3892/ijmm.2024.5364. Epub 2024 Mar 1.

DOI:10.3892/ijmm.2024.5364
PMID:38426579
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10914311/
Abstract

SET domain bifurcated 1 (SETDB1), a pivotal histone lysine methyltransferase, is transported to the cytoplasm via a chromosome region maintenance 1 (CMR1)‑dependent pathway, contributing to non‑histone methylation. However, the function and underlying mechanism of cytoplasmic SETDB1 in breast cancer remain elusive. In the present study, immunohistochemistry revealed that elevated cytoplasmic SETDB1 was correlated with lymph node metastasis and more aggressive breast cancer subtypes. Functionally, wound healing and Transwell assays showed that cytoplasmic SETDB1 is key for cell migration and invasion, as well as induction of epithelial‑mesenchymal transition (EMT), which was reversed by leptomycin B (LMB, a CMR1 inhibitor) treatment. Furthermore, RNA‑seq and metabolite detection revealed that cytoplasmic SETDB1 was associated with metabolism pathway and elevated levels of metabolites involved in the Warburg effect, including glucose, pyruvate, lactate and ATP. Immunoblotting and reverse transcription‑quantitative PCR verified that elevation of cytoplasmic SETDB1 contributed to elevation of c‑MYC expression and subsequent upregulation of lactate dehydrogenase A (LDHA) expression. Notably, gain‑ and loss‑of‑function approaches revealed that LDHA overexpression in T47D cells enhanced migration and invasion by inducing EMT, while its depletion in SETDB1‑overexpressing MCF7 cells reversed SETDB1‑induced migration and invasion, as well as the Warburg effect and EMT. In conclusion, subcellular localization of cytoplasmic SETDB1 may be a pivotal factor in breast cancer progression. The present study offers valuable insight into the novel functions and mechanisms of cytoplasmic SETDB1.

摘要

SET 结构域分隔蛋白 1（SETDB1）是一种关键的组蛋白赖氨酸甲基转移酶，通过依赖于染色体区域维持 1（CMR1）的途径被转运到细胞质中，从而促进非组蛋白甲基化。然而，细胞质 SETDB1 在乳腺癌中的功能和潜在机制仍不清楚。在本研究中，免疫组织化学分析显示，细胞质 SETDB1 水平升高与淋巴结转移和侵袭性更强的乳腺癌亚型相关。功能上，划痕愈合和 Transwell 实验表明，细胞质 SETDB1 是细胞迁移和侵袭的关键因素，并且能够诱导上皮间质转化（EMT），而 LMB（CMR1 抑制剂）处理则逆转了这一过程。此外，RNA-seq 和代谢物检测显示，细胞质 SETDB1 与代谢途径相关，并与参与瓦博格效应的代谢物水平升高有关，包括葡萄糖、丙酮酸、乳酸和 ATP。免疫印迹和逆转录定量 PCR 验证了细胞质 SETDB1 的升高导致 c-MYC 表达的升高，随后导致乳酸脱氢酶 A（LDHA）表达的上调。值得注意的是，Gain-和 Loss-of-function 方法表明，T47D 细胞中 LDHA 的过表达通过诱导 EMT 增强了迁移和侵袭能力，而在 SETDB1 过表达的 MCF7 细胞中 LDHA 的缺失则逆转了 SETDB1 诱导的迁移和侵袭以及瓦博格效应和 EMT。综上所述，细胞质 SETDB1 的亚细胞定位可能是乳腺癌进展的关键因素。本研究为细胞质 SETDB1 的新功能和机制提供了有价值的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/5c9110dde280/ijmm-53-04-05364-g06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/4be3df6d1cb5/ijmm-53-04-05364-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/46ae59fd0bff/ijmm-53-04-05364-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/80be40d6b102/ijmm-53-04-05364-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/c7ef02d0c5f5/ijmm-53-04-05364-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/fd183241d69c/ijmm-53-04-05364-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/26202a98ac8e/ijmm-53-04-05364-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/5c9110dde280/ijmm-53-04-05364-g06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/4be3df6d1cb5/ijmm-53-04-05364-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/46ae59fd0bff/ijmm-53-04-05364-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/80be40d6b102/ijmm-53-04-05364-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/c7ef02d0c5f5/ijmm-53-04-05364-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/fd183241d69c/ijmm-53-04-05364-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/26202a98ac8e/ijmm-53-04-05364-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2415/10914311/5c9110dde280/ijmm-53-04-05364-g06.jpg

相似文献

[1]
Cytoplasmic localization of SETDB1‑induced Warburg effect via c‑MYC‑LDHA axis enhances migration and invasion in breast carcinoma.

Int J Mol Med. 2024-4

[2]
SETDB1 induces epithelial‑mesenchymal transition in breast carcinoma by directly binding with Snail promoter.

Oncol Rep. 2018-11-19

[3]
SETDB1 regulates SMAD7 expression for breast cancer metastasis.

BMB Rep. 2019-2

[4]
SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression.

Cell Death Dis. 2020-5-11

[5]
Histone methyltransferase SETDB1 inhibits TGF-β-induced epithelial-mesenchymal transition in pulmonary fibrosis by regulating SNAI1 expression and the ferroptosis signaling pathway.

Arch Biochem Biophys. 2022-1-15

[6]
SETDB1 promotes glioblastoma growth via CSF-1-dependent macrophage recruitment by activating the AKT/mTOR signaling pathway.

J Exp Clin Cancer Res. 2020-10-15

[7]
Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls expression and epithelial-mesenchymal transition.

EMBO Rep. 2017-12-12

[8]
Histone methyltransferase SETDB1 promotes cells proliferation and migration by interacting withTiam1 in hepatocellular carcinoma.

BMC Cancer. 2018-5-8

[9]
The functions of SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) in biological process and disease.

Epigenetics Chromatin. 2023-12-7

[10]
Enhancer of zeste homolog 2 promotes hepatocellular cancer progression and chemoresistance by enhancing protein kinase B activation through microRNA-381-mediated SET domain bifurcated 1.

Bioengineered. 2022-3

引用本文的文献

[1]
Lactate Dehydrogenase-A-Forming LDH5 Promotes Breast Cancer Progression.

Breast Cancer (Dove Med Press). 2025-2-12

[2]
Deciphering the oncogenic network: how C1QTNF1-AS1 modulates osteosarcoma through miR-34a-5p and glycolytic pathways.

Front Oncol. 2025-1-9

本文引用的文献

[1]
SETDB1-mediated CD147-K71 di-methylation promotes cell apoptosis in non-small cell lung cancer.

Genes Dis. 2023-3-24

[2]
Beyond Warburg: LDHA activates RAC for tumour growth.

Nat Metab. 2022-12

[3]
LDHA induces EMT gene transcription and regulates autophagy to promote the metastasis and tumorigenesis of papillary thyroid carcinoma.

Cell Death Dis. 2021-4-1

[4]
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.

CA Cancer J Clin. 2021-5

[5]
Early Locoregional Breast Surgery and Survival in de novo Metastatic Breast Cancer in the Multicenter National ESME Cohort.

Ann Surg. 2023-1-1

[6]
Histone Methyltransferase SETDB1: A Common Denominator of Tumorigenesis with Therapeutic Potential.

Cancer Res. 2021-2-1

[7]
Recurrent co-alteration of HDGF and SETDB1 on chromosome 1q drives cutaneous melanoma progression and poor prognosis.

Pigment Cell Melanoma Res. 2021-5

[8]
LDHA Promotes Oral Squamous Cell Carcinoma Progression Through Facilitating Glycolysis and Epithelial-Mesenchymal Transition.

Front Oncol. 2019-12-19

[9]
Leptomycin B inhibits the proliferation, migration, and invasion of cultured gastric carcinoma cells.

Biosci Biotechnol Biochem. 2020-2

[10]
ATF7IP regulates SETDB1 nuclear localization and increases its ubiquitination.

EMBO Rep. 2019-10-2

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