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Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner.

ABSTRACT: The upstream stimulatory factor 2 (USF2) is a transcription factor implicated in several cellular processes and among them, tumor development seems to stand out. However, the data with respect to the role of USF2 in tumor development are conflicting suggesting that it acts either as tumor promoter or suppressor. Here we show that absence of USF2 promotes proliferation and migration. Thereby, we reveal a previously unknown function of USF2 in mitochondrial homeostasis. Mechanistically, we demonstrate that deficiency of USF2 promotes survival by inducing mitophagy in a ROS-sensitive manner by activating both ERK1/2 and AKT. Altogether, this study supports USF2's function as tumor suppressor and highlights its novel role for mitochondrial function and energy homeostasis thereby linking USF2 to conditions such as insulin resistance, type-2 diabetes mellitus, and the metabolic syndrome.

SUBMITTER: Chi TF

PROVIDER: S-EPMC7566946 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner.

Chi Tabughang Franklin TF Khoder-Agha Fawzi F Mennerich Daniela D Kellokumpu Sakari S Miinalainen IIkka I Kietzmann Thomas T Dimova Elitsa Y EY

Redox biology 20201007

The upstream stimulatory factor 2 (USF2) is a transcription factor implicated in several cellular processes and among them, tumor development seems to stand out. However, the data with respect to the role of USF2 in tumor development are conflicting suggesting that it acts either as tumor promoter or suppressor. Here we show that absence of USF2 promotes proliferation and migration. Thereby, we reveal a previously unknown function of USF2 in mitochondrial homeostasis. Mechanistically, we demonst ...[more]

PMID: 33059314

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Project description:BackgroundHypoxic microenvironments play a significant role in the progression of colorectal cancer (CRC). Silencing information regulator 1 (SIRT1), a class III histone deacetylase, modulates the multiple biological behaviors of cancer. However, its role in CRC remains unclear. This study aims to explore the role of SIRT1 in CRC migration and invasion under hypoxia.MethodsSIRT1 protein and mRNA levels were detected by Western blotting and real-time PCR in CRC cells exposed to hypoxia (1% O2). The migration and invasion abilities of SW480 and HCT116 cells with SIRT1 overexpression or knockdown were studied with transwell assays, and the results were confirmed by those of treatment with specific SIRT1 activator (SRT1720) and inhibitor (EX527). The dual-luciferase reporter systems with a series of SIRT1 promoter truncations were used to analyze their transcriptional activities, respectively. After a bioinformatic analysis of potential transcription factors, the direct interaction between the transcription factor and SIRT1 promoter was determined by chromatin immunoprecipitation (ChIP) assays. Western blot and real-time PCR assays were used to detect the activation and acetylation levels of the NF-κB pathway.ResultsThe protein and mRNA levels of SIRT1 were significantly decreased under hypoxia, and these effects were replicated by cobalt chloride treatment. Hypoxia promoted cell migration and invasion, which were impeded by the overexpression or activation of SIRT1 and promoted by the knockdown or inhibition of SIRT1. The dual-luciferase reporter gene and ChIP analyses revealed that the core regulatory elements located 100 bp upstream of the SIRT1 promoter and early growth response factor 1 (EGR1) could interact with this DNA sequence. Subsequent rescue experiments suggested that EGR1 was essential for hypoxia-mediated SIRT1 transcriptional suppression. Western blot analyses demonstrated that SIRT1 overexpression eliminated the p65 acetylation induced by hypoxia along with the decreased MMP-2/-9, suggesting that NF-κB was a direct downstream target of SIRT1 and might regulate cell migration and invasion through MMP-2/-9.ConclusionsOur results establish for the first time that EGR1 plays an important role in regulating SIRT1 expression under hypoxia. Hypoxia promotes CRC cell migration and invasion in a SIRT1-dependent manner. And a potential SIRT1/NF-κB/MMP-2/-9 axis modulates this process.

Dataset Information

Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner.

Publications

Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner.

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