TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice

Jiang, Shiming; Minter, Lindsey Cauthen; Stratton, Sabrina A.; Yang, Peirong; Abbas, Hussein A.; Akdemir, Zeynep Coban; Pant, Vinod; Post, Sean M.; Gagea, Mihai; Lee, Richard G.; Lozano, Guillermina; Barton, Michelle C.

doi:10.1016/j.jhep.2014.09.026

Cited by 66 publications

(55 citation statements)

References 41 publications

(59 reference statements)

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“…Hao2 is strongly induced in E1/E2-KO male liver, but to only ~60% the level of control (wild-type) female liver, and this increase in expression may not be not sufficient to counteract the severe liver injury generated by loss of Ezh1/Ezh2. Furthermore, other female-biased genes that have been recognized as tumor suppressors in HCC, such as Trim24 [71, 72], are not up-regulated in male E1/E2-KO liver. Further studies are needed to determine the extent to which the higher expression of such liver disease-protective genes in female liver contributes to sex-differences in liver fibrosis and liver disease.…”

Section: Discussionmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona

Bae

Hennighausen

et al. 2019

Preprint

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31Background: Sex differences in the incidence and progression of many liver diseases, including liver 32 fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of 33 genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary 34 growth hormone secretion, which controls a transcriptional regulatory network operative in the context 35 of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive 36 chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous 37 catalytic subunits Ezh1 and Ezh2, at many strongly female-biased genes in male mouse liver, but not 38 at male-biased genes in female liver. Results: We used Ezh1-knockout mice with a hepatocyte-39 specific knockout of Ezh2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role 40 in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant 41 loss of sex-biased gene expression, particularly in male liver, where many female-biased genes 42 increased in expression while male-biased genes showed decreased expression. The associated loss 43 of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also 44 more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were 45 induced in Ezh1/Ezh2-deficient livers, which may contribute to the increased sensitivity of these mice 46 to hepatotoxin-induced liver pathology. Conclusions: Ezh1/Ezh2-catalyzed H3K27-trimethyation is 47 thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling 48 phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of 49 the sex-bias in liver disease susceptibility. Background 52Liver disease shows marked sex differences. Hepatocellular carcinoma incidence and mortality is 53 three times higher in men than in women [1, 2], and male mice are more susceptible to chemical-54 induced hepatic carcinogenesis [3]. Males are also more susceptible to non-alcoholic fatty liver 55 disease, non-alcoholic steatohepatitis and liver fibrosis than females [4][5][6][7][8]. Underlying these sex-biased Lau-Corona et alPage 5 3/13/19 liver. Hepatic Ezh1/Ezh2 deficiency is also shown to down regulate many male-biased genes, 106presumed as a secondary response to the disruption of female-biased gene expression. Finally, we 107show that many genes associated with liver fibrosis and liver carcinogenesis are differentially 108 responsive to the loss of Ezh1/Ezh2 in male compared to female liver, which may contribute to the 109 observed sex-differences in the incidence and progression of liver cancer. 110 111 Methods 112 Animal tissues. Livers from 7-week-old male and female Ezh1-knockout mice with a hepatocyte-113 specific knockout of Ezh2 (E1/E2-KO mice, also designated Double-knockout (DKO) in the figures 114 and tables) and their age and sex...

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Section: Discussionmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona

Bae

Hennighausen

et al. 2019

Preprint

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“…L iv e r (T C Analyses of genomic data of tumors with high levels of MDM4 and p53 mutation or deletion from data sets accessed and prepared using the cBioPortal for Cancer Genetics (www.cbio portal.org) (Cerami et al 2012;Gao et al 2013 (Hakem et al 2011;Migliorini et al 2011;Jiang et al 2015), studies have shown strong evidence of regulation in vitro. The in vivo models to date have modeled loss of these enzymes, not overexpression, which would be expected to better mimic the pathological state for a negative regulator of p53 during tumorigenesis.…”

Section: Cross-cancer Alteration Summary For Mdm4mentioning

confidence: 99%

Attenuating the p53 Pathway in Human Cancers: Many Means to the Same End

Wasylishen

Lozano

2016

Cold Spring Harb Perspect Med

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111

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The p53 pathway is perturbed in the majority of human cancers. Although this most frequently occurs through the direct mutation or deletion of p53 itself, there are a number of other alterations that can attenuate the pathway and contribute to tumorigenesis. For example, amplification of important negative regulators, MDM2 and MDM4, occurs in a number of cancers. In this work, we will review both the normal regulation of the p53 pathway and the different mechanisms of pathway inhibition in cancer, discuss these alterations in the context of the global genomic analyses that have been conducted across tumor types, and highlight the translational implications for cancer diagnosis and treatment.

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“…In this study, we focused on TRIM24, a newly identified TRIM family member as a binding partner of dysbindin in our yeast two-hybrid (Y2H) screen. TRIM24 has been studied thus far only in the context of cancer (32)(33)(34). TRIM24 is known to be interacting with tumor protein 53 (p53), leading to its degradation by ubiquitination and hence affecting genomic stability, cell cycle arrest, and apoptosis (35).…”

mentioning

confidence: 99%

TRIM24 protein promotes and TRIM32 protein inhibits cardiomyocyte hypertrophy via regulation of dysbindin protein levels

Borlepawar

Rangrez

Bernt

et al. 2017

Journal of Biological Chemistry

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We have previously shown that dysbindin is a potent inducer of cardiomyocyte hypertrophy via activation of Rho-dependent serum-response factor (SRF) signaling. We have now performed a yeast two-hybrid screen using dysbindin as bait against a cardiac cDNA library to identify the cardiac dysbindin interactome. Among several putative binding proteins, we identified tripartite motif-containing protein 24 (TRIM24) and confirmed this interaction by co-immunoprecipitation and co-immunostaining. Another tripartite motif (TRIM) family protein, TRIM32, has been reported earlier as an E3 ubiquitin ligase for dysbindin in skeletal muscle. Consistently, we found that TRIM32 also degraded dysbindin in neonatal rat ventricular cardiomyocytes as well. Surprisingly, however, TRIM24 did not promote dysbindin decay but rather protected dysbindin against degradation by TRIM32. Correspondingly, TRIM32 attenuated the activation of SRF signaling and hypertrophy due to dysbindin, whereas TRIM24 promoted these effects in neonatal rat ventricular cardiomyocytes. This study also implies that TRIM32 is a key regulator of cell viability and apoptosis in cardiomyocytes via simultaneous activation of p53 and caspase-3/-7 and inhibition of X-linked inhibitor of apoptosis. In conclusion, we provide here a novel mechanism of post-translational regulation of dysbindin and hypertrophy via TRIM24 and TRIM32 and show the importance of TRIM32 in cardiomyocyte apoptosis .

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TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice

Cited by 66 publications

References 41 publications

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Attenuating the p53 Pathway in Human Cancers: Many Means to the Same End

TRIM24 protein promotes and TRIM32 protein inhibits cardiomyocyte hypertrophy via regulation of dysbindin protein levels

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