MTA2 triggered R-loop trans-regulates BDH1-mediated β-hydroxybutyrylation and potentiates propagation of hepatocellular carcinoma stem cells

Zhang, Heng; Chang, Zhi; Qin, Lu-Ning; Liang, Bin; Qiao, Kun; Yang, Cheng; Liu, Yanrong; Zhou, Honggang; Sun, Tao

doi:10.1038/s41392-021-00464-z

Cited by 33 publications

(30 citation statements)

References 5 publications

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“…In a word, the role of KD might very differs from that of Bdh1 in liver and Bdh1 would functions as different roles in different physiological conditions. Given that Bdh1 can also mediates β-hydroxybutyrylation to regulate gene expression in hepatocellular carcinoma stem cells [ 26 ], continued studies aimed at identifying new mechanisms mediated by Bdh1 in MAFLD are desperately needed.…”

Section: Discussionmentioning

confidence: 99%

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Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model

Teng

et al. 2022

Cell Death Discov.

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In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease “MAFLD” as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an important metabolic regulator in liver. However, the role of Bdh1 in MAFLD is unclear. In this study, we used the transgenic db/db mice as a MAFLD mouse model and observed the downregulated expression of Bdh1 in fatty liver. In addition, expression of Bdh1 was also reduced by palmitic acid (PA) treatment in LO2 cells. Bdh1 knockdown led to ROS overproduction and ROS-induced inflammation and apoptosis in LO2 cells, while Bdh1 overexpression protected LO2 cells from lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated βOHB metabolism inhibits ROS overproduction by activation of Nrf2 through enhancement of metabolic flux composed of βOHB-AcAc-succinate-fumarate. Notably, adeno-associated virus (AAV)-mediated Bdh1 overexpression successfully reversed the hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice. In conclusion, our study revealed a Bdh1-mediated molecular mechanism in pathogenesis of metabolic dysfunction related liver disease and identified Bdh1 as a novel potential therapeutic target for MAFLD.

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Section: Discussionmentioning

confidence: 99%

“…In liver, deletion of Bdh1 causes low ketone body level and fatty liver during fasting [ 25 ]. Moreover, Bdh1-mediated β-hydroxybutyrylation potentiates propagation of hepatocellular carcinoma stem cells [ 26 ]. However, the role of Bdh1-mediated ketone body metabolism in the pathogenesis of MAFLD is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model

Teng

et al. 2022

Cell Death Discov.

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“…Loss of intestinal HMGCS2 impairs the aggregation of H3K9bhb and affects H3K9bhb-related metabolic gene programs ( 48 ). However, inhibition of BDH1 resulted in the aggregation of BHB and the increase of H3K9bhb, which promoted the proliferation of hepatocellular carcinoma stem cells ( 49 ). Moreover, metabolic stress induced BHB is a natural endogenous HDAC inhibitor, which induces H3K9ac and H3K4ac ( 50 , 51 ).…”

Section: The Discovery and Recent Advances Of Histone Kbhbmentioning

confidence: 99%

Function and mechanism of histone β-hydroxybutyrylation in health and disease

Zhou

Cheng

et al. 2022

Front. Immunol.

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Histone post-translational modifications (HPTMs) are essential epigenetic mechanisms that affect chromatin-associated nuclear processes without altering the DNA sequence. With the application of mass spectrometry-based proteomics, novel histone lysine acylation, such as propionylation, butyrylation, crotonylation, malonylation, succinylation, glutarylation, and lactoylation have been successively discovered. The emerging diversity of the lysine acylation landscape prompted us to investigate the function and mechanism of these novel HPTMs in health and disease. Recently, it has been reported that β-hydroxybutyrate (BHB), the main component of the ketone body, has various protective roles beyond alternative fuel provision during starvation. Histone lysine β-hydroxybutyrylation (Kbhb) is a novel HPTMs identified by mass spectrometry, which regulates gene transcription in response to carbohydrate restriction or elevated BHB levels in vivo and vitro. Recent studies have shown that histone Kbhb is strongly associated with the pathogenesis of metabolic cardiovascular diseases, kidney diseases, tumors, neuropsychiatric disorders, and metabolic diseases suggesting it has different functions from histone acetylation and methylation. This review focuses on the writers, erasers, sites, and underlying functions of histone Kbhb, providing a glimpse into their complex regulation mechanism.

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“…In HCT116 cells, β-HB-mediated p53 Kbhb at K120, K319, and K370 sites results in lower levels of p53 acetylation and consequently, decreased activity of p53, leading to weakened tumor-suppressive function (Liu et al, 2019). MTA2 can transcriptionally regulate BDH1-mediated histone β-HB modification through the R-loop structure in synergy with HDAC2/CHD4 and promote the proliferation of hepatoma stem cells (Zhang et al, 2021).…”

Section: β-Hydroxybutyratementioning

confidence: 99%

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

Huo

Zhang

Huang

et al. 2021

Front. Cell Dev. Biol.

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Epigenetic modifications and metabolism are two fundamental biological processes. During tumorigenesis and cancer development both epigenetic and metabolic alterations occur and are often intertwined together. Epigenetic modifications contribute to metabolic reprogramming by modifying the transcriptional regulation of metabolic enzymes, which is crucial for glucose metabolism, lipid metabolism, and amino acid metabolism. Metabolites provide substrates for epigenetic modifications, including histone modification (methylation, acetylation, and phosphorylation), DNA and RNA methylation and non-coding RNAs. Simultaneously, some metabolites can also serve as substrates for nonhistone post-translational modifications that have an impact on the development of tumors. And metabolic enzymes also regulate epigenetic modifications independent of their metabolites. In addition, metabolites produced by gut microbiota influence host metabolism. Understanding the crosstalk among metabolism, epigenetic modifications, and gene expression in cancer may help researchers explore the mechanisms of carcinogenesis and progression to metastasis, thereby provide strategies for the prevention and therapy of cancer. In this review, we summarize the progress in the understanding of the interactions between cancer metabolism and epigenetics.

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MTA2 triggered R-loop trans-regulates BDH1-mediated β-hydroxybutyrylation and potentiates propagation of hepatocellular carcinoma stem cells

Cited by 33 publications

References 5 publications

Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model

Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model

Function and mechanism of histone β-hydroxybutyrylation in health and disease

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

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