Transcriptional Regulation of HMOX1 Gene in Hezuo Tibetan Pigs: Roles of WT1, Sp1, and C/EBPα

Wang, Wei; Yang, Qiaoli; Xie, Kaihui; Wang, Pengfei; Luo, Ruirui; Yan, Zunqiang; Gao, Xiaoli; Zhang, Bo; Huang, Xiaoyu; Gun, Shuangbao

doi:10.3390/genes11040352

Cited by 5 publications

(5 citation statements)

References 49 publications

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“…It remains to be determined whether zoledronic acid and EF24 activate the same or different pathway to upregulate HMOX1 in osteosarcoma cells. HMOX1 gene transcription can be subjected to complex regulation involving different transcription factors such as WT1, Sp1, C/EBPα, and Nrf2 ( Wang et al, 2020 ; Zhang et al, 2021 ). Further studies are required to delineate which of these factors mediates zoledronic acid-induced increase in HMOX1 mRNA expression in osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid induces ferroptosis by reducing ubiquinone and promoting HMOX1 expression in osteosarcoma cells

et al. 2023

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Aims: Ferroptosis plays important roles in tumorigenesis and cancer therapy. Zoledronic acid is known to inhibit the activity of farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. We examined whether zoledronic acid can inhibit the growth of osteosarcoma cells by inducing ferroptosis.Methods: Cell viability was analyzed by using CCK8 reagent and counting cells with trypan blue exclusion. Ferroptosis markers including lipid peroxide and PTGS2 expression were examined by flow cytometry, western blot, and quantitative PCR analyses. Cellular ubiquinone content was determined using high performance liquid chromatography. Ferrostatin-1 and RSL3 were used as the ferroptosis inhibitor and inducer respectively.Results: Zoledronic acid treatment decreased cell viability and promoted the increase in lipid peroxide content and PTGS2 expression. Addition of ferrostatin-1 reverted these effects of zoledronic acid on osteosarcoma cells, supporting a role of zoledronic acid in inducing ferroptosis. Mechanistically, zoledronic acid significantly decreased ubiquinone, a metabolite of the mevalonate pathway. Treating cells with exogenous ubiquinone prevented zoledronic acid-induced ferroptosis and decrease in the growth of osteosarcoma cells. In addition, zoledronic acid enhanced the expression of HMOX1, whereas knockdown of HMOX1 inhibited the zoledronic acid-induced increase in lipid peroxide level and decrease in cell growth. Finally, zoledronic acid together with RSL3 significantly enhanced the inhibitory effect on the growth of osteosarcoma cells.Conclusion: Our results indicate that zoledronic acid induces ferroptosis by decreasing ubiquinone content and promoting HMOX1 expression in osteosarcoma cells. Zoledronic acid together with ferroptosis inducer may be a promising new strategy for the treatment of osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Zoledronic acid induces ferroptosis by reducing ubiquinone and promoting HMOX1 expression in osteosarcoma cells

et al. 2023

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“…HMOX1 is a stress‐inducible enzyme 32 . The HMOX1 promoter regulates transcription through polymorphisms in response to oxidative stress 33 .…”

Section: Discussionmentioning

confidence: 99%

“…HMOX1 is a stress-inducible enzyme. 32 The HMOX1 promoter regulates transcription through polymorphisms in response to oxidative stress. 33 In addition, BACH1 has an endogenous heme ligand that investigated the levels of plasma metabolites in patients with lumbar disc herniation and found that glutamate, aspartate, and glycine levels were elevated, and the content of glucose 1-phosphate was diminished.…”

Section: Discussionmentioning

confidence: 99%

BACH1 promotes intervertebral disc degeneration by regulating HMOX1/GPX4 to mediate oxidative stress, ferroptosis, and lipid metabolism in nucleus pulposus cells

Yao

Cai

Wan

et al. 2023

The Journal of Gene Medicine

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Background: Intervertebral disc degeneration (IDD) is a primary health problem worldwide that involves oxidative stress, ferroptosis, and lipid metabolism. However, the underlying mechanism remains unclear. We investigated whether the transcription factor BTB and CNC homology 1 (BACH1) affected IDD progression by regulating HMOX1/GPX4-mediated ferroptosis and lipid metabolism in nucleus pulposus cells (NPCs).Methods: A rat IDD model was created to detect BACH1 expression in intervertebral disc tissues. Next, rat NPCs were isolated and treated with tert-butyl hydroperoxide (TBHP). BACH1, HMOX1, and GPX4 were knocked down, and oxidative stress and ferroptosis-related marker levels were examined. The binding of BACH1 to HMOX1 and of BACH1 to GPX4 was verified using chromatin immunoprecipitation (ChIP).Finally, untargeted lipid metabolism analysis was performed.Results: An IDD model was successfully created, and BACH1 activity was found to be enhanced in the rat IDD tissues. BACH1 inhibited TBHP-induced oxidative stress and oxidative stress-induced ferroptosis in NPCs. Simultaneously, ChIP verified that BACH1 protein bound to HMOX1 and targeted the HMOX1 transcription inhibition to affect oxidative stress in NPCs. ChIP also verified that BACH1 bound to GPX4 and targeted the GPX4 inhibition to affect ferroptosis in NPCs. Finally, BACH1 inhibition in vivo improved IDD and affected lipid metabolism. Conclusions:The transcription factor BACH1 promoted IDD by regulating HMOX1/ GPX4 to mediate oxidative stress, ferroptosis, and lipid metabolism in NPCs.

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“…To explore the factors regulating RIP2 expression activity, we firstly analyzed and identified the core promoter region of chicken RIP2 . Luciferase reporter gene vector utilized in this study is a common method for many studies of the promoter activity and core regulatory regions [ 43 , 44 , 45 ]. Meanwhile, chicken HD11 and DF1 cells were used as experimental models to double check the promoter activity of RIP2 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of RIP2 Gene by NFIB Is Associated with Cellular Immune and Inflammatory Response to APEC Infection

Sun

Tan

et al. 2022

IJMS

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Avian pathogenic E. coli (APEC) can cause localized or systemic infection, resulting in large economic losses per year, and impact health of humans. Previous studies showed that RIP2 (receptor interacting serine/threonine kinase 2) and its signaling pathway played an important role in immune response against APEC infection. In this study, chicken HD11 cells were used as an in vitro model to investigate the function of chicken RIP2 and the transcription factor binding to the RIP2 core promoter region via gene overexpression, RNA interference, RT-qPCR, Western blotting, dual luciferase reporter assay, CHIP-PCR, CCK-8, and flow cytometry assay following APEC stimulation. Results showed that APEC stimulation promoted RIP2 expression and cells apoptosis, and inhibited cells viability. Knockdown of RIP2 significantly improved cell viability and suppressed the apoptosis of APEC-stimulated cells. Transcription factor NFIB (Nuclear factor I B) and GATA1 (globin transcription factor 1) binding site was identified in the core promoter region of RIP2 from −2300 bp to −1839 bp. However, only NFIB was confirmed to be bound to the core promoter of RIP2. Overexpression of NFIB exacerbated cell injuries with significant reduction in cell viability and increased cell apoptosis and inflammatory cytokines levels, whereas opposite results were observed in NFIB inhibition treatment group. Moreover, RIP2 was up-regulated by NFIB overexpression, and RIP2 silence mitigated the effect of NFIB overexpression in cell apoptosis, inflammation, and activation of NFκB signaling pathways. This study demonstrated that NFIB overexpression accelerated APEC-induced apoptosis and inflammation via up-regulation of RIP2 mediated downstream pathways in chicken HD11 cells.

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Transcriptional Regulation of HMOX1 Gene in Hezuo Tibetan Pigs: Roles of WT1, Sp1, and C/EBPα

Cited by 5 publications

References 49 publications

Zoledronic acid induces ferroptosis by reducing ubiquinone and promoting HMOX1 expression in osteosarcoma cells

Zoledronic acid induces ferroptosis by reducing ubiquinone and promoting HMOX1 expression in osteosarcoma cells

BACH1 promotes intervertebral disc degeneration by regulating HMOX1/GPX4 to mediate oxidative stress, ferroptosis, and lipid metabolism in nucleus pulposus cells

Transcriptional Regulation of RIP2 Gene by NFIB Is Associated with Cellular Immune and Inflammatory Response to APEC Infection

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