RNF40 epigenetically modulates glycolysis to support the aggressiveness of basal-like breast cancer

Prokakis, Evangelos; Jansari, Shaishavi; Boshnakovska, Angela; Wiese, Maria; Kusch, Kathrin; Kramm, Christof; Dullin, Christian; Rehling, Peter; Glatzel, Markus; Pantel, Klaus; Wikman, Harriet; Johnsen, Steven A.; Gallwas, Julia; Wegwitz, Florian

doi:10.1038/s41419-023-06157-5

Cited by 3 publications

(1 citation statement)

References 83 publications

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“…RNF40 has been demonstrated to monoubiquitinate histone H2B at lysine 120 (H2Bub1) via its E3 ligase activity, which is required for gene regulation at the epigenetic level and essential for several biological functions, including cell reprogramming and metabolism [ 29 – 31 ]. Particularly, loss or low expression of RNF40 is negatively correlated with the expression levels of genes enriched in glycolysis, which supports a pivotal role of RNF40 in maintaining the glycolytic program and promoting the malignant behavior of breast cancer [ 31 ]. However, less is known about the role of RNF40 in the cytoplasm and its potential targets involved in the regulation of lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

LIMA1 links the E3 ubiquitin ligase RNF40 to lipid metabolism

Liu,

Fan,

Abudukeremu

et al. 2024

Cell Death Discov.

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LIMA1 is a LIM domain and Actin binding 1 protein that acts as a skeleton protein to promote cholesterol absorption, which makes it an ideal target for interfering with lipid metabolism. However, the detailed regulation of LIMA1 remains unclear. Here, we identified that ring finger protein 40 (RNF40), an E3 ubiquitin ligase previously known as an epigenetic modifier to increase H2B ubiquitination, mediated the ubiquitination of LIMA1 and thereby promoted its degradation in a proteasome-dependent manner. Fraction studies revealed that the 1–166aa fragment of LIMA1 was indispensable for the interaction with RNF40, and at least two domains of RNF40 might mediate the association of RNF40 with LIMA1. Notably, treatment with simvastatin dramatically decreased the levels of CHO and TG in control cells rather than cells with overexpressed LIMA1. Moreover, RNF40 significantly decreased lipid content, which could be reversed by LIMA1 overexpression. These findings suggest that E3 ubiquitin ligase RNF40 could directly target LIMA1 and promote its protein degradation in cytoplasm, leading to the suppression of lipid accumulation mediated by LIMA1. Collectively, this study unveils that RNF40 is a novel E3 ubiquitin ligase of LIMA1, which underpins its high therapeutic value to combat dysregulation of lipid metabolism.

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Section: Discussionmentioning

confidence: 99%

LIMA1 links the E3 ubiquitin ligase RNF40 to lipid metabolism

Liu,

Fan,

Abudukeremu

et al. 2024

Cell Death Discov.

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Hypoxia-inducible factor 1 recruits FACT and RNF20/40 to mediate histone ubiquitination and transcriptional activation of target genes

Lyu,

Yang,

Talwar

et al. 2024

Cell Reports

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ZFP64 drives glycolysis-mediated stem cell-like properties and tumorigenesis in breast cancer

Sun,

Liu,

Hou

et al. 2024

Biol Direct

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Background Breast cancer (BC) is a great clinical challenge because of its aggressiveness and poor prognosis. Zinc Finger Protein 64 (ZFP64), as a transcriptional factor, is responsible for the development and progression of cancers. This study aims to investigate whether ZFP64 regulates stem cell-like properties and tumorigenesis in BC by the glycolytic pathway. Results It was demonstrated that ZFP64 was overexpressed in BC specimens compared to adjacent normal tissues, and patients with high ZFP64 expression had shorter overall survival and disease-free survival. The analysis of the association of ZFP64 expression with clinicopathological characteristics showed that high ZFP64 expression is closely associated with N stage, TNM stage, and progesterone receptor status. Knockdown of ZFP64 suppressed the viability and colony formation capacity of BC cells by CCK8 and colony formation assays. The subcutaneous xenograft models revealed that ZFP64 knockdown reduced the volume of formatted tumors, and decreased Ki67 expression in tumors. The opposite effects on cell proliferation and tumorigenesis were demonstrated by ZFP64 overexpression. Furthermore, we suggested that the stem cell-like properties of BC cells were inhibited by ZFP64 depletion, as evidenced by the decreased size and number of formatted mammospheres, the downregulated expressions of OCT4, Nanog, and SOX2 proteins, as well as the reduced proportion of CD44 + /CD24 − subpopulations. Mechanistically, glycolysis was revealed to mediate the effect of ZFP64 using mRNA-seq analysis. Results showed that ZFP64 knockdown blocked the glycolytic process, as indicated by decreasing glycolytic metabolites, inhibiting glucose consumption, and reducing lactate and ATP production. As a transcription factor, we identified that ZFP64 was directly bound to the promoters of glycolysis-related genes (ALDOC, ENO2, HK2, and SPAG4), and induced the transcription of these genes by ChIP and dual-luciferase reporter assays. Blocking the glycolytic pathway by the inhibition of glycolytic enzymes ENO2/HK2 suppressed the high proliferation and stem cell-like properties of BC cells induced by ZFP64 overexpression. Conclusions These data support that ZFP64 promotes stem cell-like properties and tumorigenesis of BC by activating glycolysis in a transcriptional mechanism. Supplementary Information The online version contains supplementary material available at 10.1186/s13062-024-00533-7.

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RNF40 epigenetically modulates glycolysis to support the aggressiveness of basal-like breast cancer

Cited by 3 publications

References 83 publications

LIMA1 links the E3 ubiquitin ligase RNF40 to lipid metabolism

LIMA1 links the E3 ubiquitin ligase RNF40 to lipid metabolism

Hypoxia-inducible factor 1 recruits FACT and RNF20/40 to mediate histone ubiquitination and transcriptional activation of target genes

ZFP64 drives glycolysis-mediated stem cell-like properties and tumorigenesis in breast cancer

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