Dataset Information

Blocking TRIM47-mediated HNF4α degradation Suppress Hepatocellular Carcinoma Progression

ABSTRACT: Previous studies have highlighted the downregulation of hepatocyte nuclear factor 4α (HNF4α) as a critical event in the pathogenesis of HCC. However, the mechanism of its degradation in HCC remains unclear. Tripartite motif 47 (TRIM47), a typical E3 ubiquitin ligase of the TRIM family, implicates various tumors, yet its specific role in HCC progression is not fully elucidated. In this study, HNF4α was identified as a potential target of TRIM47 by using co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis. TRIM47 facilitates the degradation of HNF4α by mediating K48-linked ubiquitination at lysine 470. Abrogation of HNF4α ubiquitination attenuated the promoting effect of TRIM47 on HCC malignancy. Molecular docking studies and Co-IP experiments revealed that K342, W349, and E353 of HNF4α, along with K534 and K600 of TRIM47 are crucial for their interaction. A small molecular, CZ-2401, was selected as a potent inhibitor of the TRIM47-HNF4α interaction through virtual screening and pharmacological activity validation. CZ-2401 effectively stabilizes HNF4α protein in HCC cells and ameliorates TRIM47-driven HCC progression in vivo. Taking together, our research elucidates that targeting TRIM47-HNF4α interaction is a potential therapeutic strategy for HCC, and identifies CZ-2401 as a potent inhibitor of HNF4α degradation and a promising candidate for HCC therapy.

ORGANISM(S): Homo Sapiens

SUBMITTER: Hu Zhou

PROVIDER: PXD062446 | iProX | Tue Apr 01 00:00:00 GMT+01:00 2025

REPOSITORIES: iProX

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Blocking TRIM47-mediated HNF4α degradation suppresses hepatocellular carcinoma progression.

Hong Huanyu H Xiao Mengchao M Qian Hui H Tan Siqi S Wu Sihan S Liu Fang F Hong Xialu X Liu Shuqing S Ding Chenhong C Wang Keqi K Xie Weifen W Zhang Xin X

Acta pharmaceutica Sinica. B 20251101 2

Previous studies have highlighted the downregulation of hepatocyte nuclear factor 4alpha (HNF4α) as a critical event in the pathogenesis of HCC. However, the mechanism of its degradation in HCC remains unclear. Tripartite motif 47 (TRIM47), a typical E3 ubiquitin ligase of the TRIM family, has been implicated in various tumors, yet its specific role in HCC progression is not fully elucidated. In this study, HNF4α was identified as a potential target of TRIM47 by using co-immunoprec ...[more]

PMID: 41685142

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Project description:Our previous studies have implicated CHIP as a co-chaperone/ubiquitin ligase, whose activities yield protection against stress-induced apoptotic events. In this report, we demonstrate a stress-dependent interaction between CHIP (carboxyl terminus of Hsp70-interacting protein) and Daxx, death domain-associated protein. This interaction interferes with the stress-dependent association of HIPK2 with Daxx, blocking phosphorylation of serine 46 in p53 and inhibiting the p53-dependent apoptotic program. Microarray analysis confirmed suppression of the p53-dependent transcriptional portrait in CHIP (+/+) but not in CHIP (-/-) heat shocked MEFs. The interaction between CHIP and Daxx results in ubiquitination of Daxx which is then partitioned to an insoluble compartment of the cell. In vitro ubiquitination of Daxx by CHIP revealed that Ub chain formation utilizes non canonical lysine linkages associated with resistance to proteasomal degradation. CHIP's ubiquitination of Daxx utilizes lysines 630 and 631 and competes with the cell's sumoylation machinery at these residues. These studies implicate CHIP as a stress-dependent regulator of Daxx that counters Daxx's pro-apoptotic influence in the cell. By abrogating p53-dependent apoptotic pathways and by ubiquitination competitive with Daxx sumoylation, CHIP integrates the cell's proteotoxic stress response with cell cycle pathways that influence cell survival. Keywords: p53, apoptosis, cell stress, ubiquitination We utilized a âsample x referenceâ experimental design strategy in which RNA extracted from mouse embryonic fibroblasts was hybridized to the microarray slide in the presence of labeled Universal Mouse Reference RNA (UMRR, Stratagene, LaJolla, CA). A total of 24 RNA samples were used in this analysis. Briefly, five hundred nanograms of total RNA were used for gene expression profiling following reverse transcription and T-7 polymerase-mediated amplification/labeling with Cyanine-5 CTP. Labeled subject cRNA was co-hybridized to Agilent G4112F Whole Mouse Genome 4x44K oligonucleotide arrays with equimolar amounts of Cyanine-3 labeled UHRR. Slides were hybridized, washed, and scanned on an Axon 4000b microarray scanner. The data were processed using Feature Extaction software (Agilent, Santa Clara, CA).

Dataset Information

Blocking TRIM47-mediated HNF4α degradation Suppress Hepatocellular Carcinoma Progression

Publications

Blocking TRIM47-mediated HNF4<i>α</i> degradation suppresses hepatocellular carcinoma progression.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Blocking TRIM47-mediated HNF4α degradation Suppress Hepatocellular Carcinoma Progression

Publications

Blocking TRIM47-mediated HNF4&lt;i&gt;α&lt;/i&gt; degradation suppresses hepatocellular carcinoma progression.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Blocking TRIM47-mediated HNF4<i>α</i> degradation suppresses hepatocellular carcinoma progression.