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P62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells

ABSTRACT: p62/SQSTM1 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCC). Although p62 was proposed to participate in formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression level in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, c-Myc induction and protection of HCC-initiating cells from oxidative stress-induced death.

ORGANISM(S): Mus musculus

PROVIDER: GSE77323 | GEO | 2016/11/23

SECONDARY ACCESSION(S): PRJNA310105

REPOSITORIES: GEO

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p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis and liver cancer

Project description:Hepatic stellate cells (HSC) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSC inhibits liver inflammation and fibrosis. Here we show that p62/SQSTM1, a protein that is upregulated in liver parenchymal cells but downregulated in HCC-associated HSC, negatively regulates HSC activation. Total body or HSC-specific p62 ablation potentiates HSC activation and enhances inflammation, fibrosis and HCC progression. We demonstrate that p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target genes recruitment. Loss of p62 in HSC impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSC, whose activation supports HCC development.

2016-11-23 | GSE78760 | GEO

p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells.

Project description:p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death.

| S-EPMC4907799 | biostudies-literature

p62/SQSTM1 iCLIP in Human Huh-7 cells

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Human, melanoma, p62/SQSTM1, quantitative proteomics

Project description:p62/SQSTM1 was identified as a modulator of metastatic genes selectively enriched in melanoma in autophagy independent manner. iTRAQ quantitative proteomic approach was performed in melanoma cell lines (SK-Mel-103 and UACC-62) deficient for p62 to identify downstream effectors of p62. Similar studies were performed for ATG5, a core component of autophagy, as a reference for autophagy-associated changes in protein abundance. Additionally, melanoma cells were subjected to affinity purification (AP-MS) to identify the interactors of p62. Overall, these studies underscore a novel unexpected role of p62 regulating the stability of prometastatic factors via the interaction with RNA Binding Proteins, thus leading to the inhibition of protein translation.

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p62 sustains a protumorigenic gene signature in melanoma opposing mRNA-dependent decay [SKMEL_3days]

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p62 sustains a protumorigenic gene signature in melanoma opposing mRNA-dependent decay [UACC62_3days]

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p62 sustains a protumorigenic gene signature in melanoma opposing mRNA-dependent decay [SKMEL_6days]

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Project description:Squestosome 1 (SQSTM1), also known as p62, is a multi-functional adaptor protein known for its pleotropic roles in autophagy, proteostasis, inflammation and cancer. Recently, p62 has emerged as an important modulator of protein quality control and aging. However, its role in the heart is not well understood. Our understanding of the role of p62 in the heart has been limited to the indirect assessment of its function in the setting of autophagy inhibition or proteotoxic stress. However, whether p62 is required to maintain cardiac function at rest or in response to stress has not been explored. Here we investigated the functional consequence of cardiac p62 deletion in the absence of other contributing phenotypic and systemic factors observed in the whole-body p62 deleted mice. Lack of cardiomyocytes p62 precipitated cardiac aging in mice and was associated with reduced contractile function and a progressive development of cardiac hypertrophy and fibrosis. Transcriptomic analysis of p62-deleted heart revealed a selective impairment in Nrf2 transcription, which was confirmed in the hearts of p62cKO mice. We further showed that absence of p62 in adult mice resulted in excessive oxidative stress and cell death when mice were rendered hypoxic. To gain mechanistic insights, we employed loss and gain of p62 function in H9c2 cardiomyoblasts and showed a sustained reduction in Nrf2 protein expression, nuclear translocation and transcriptional activity in p62-deficient cells. Mechanistically, p62-deficient cells exhibited an increase in proteasome-mediated Nrf2 degradation. In contrast, gain of p62 function led to Nrf2 stabilization and transcriptional activity.

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