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Inhibition of Heme Oxygenase 1 Suppresses Growth, Migration, and Invasion, and Regulates Tumor-Infiltrating CD8+ T Cells and in Uveal Melanoma.

PURPOSE: Metastatic uveal melanoma (UM) treatment is difficult, and effective treatments are urgently needed. We aimed to explore the role of heme oxygenase 1 (HO-1) in UM and provide new therapeutic strategies for UM. METHODS: Bioinformatics was used to analyze the relationship between HMOX1 and immunity in UM and other tumors. Cell Counting Kit-8, Western blot, immunofluorescence staining, wound healing, and Transwell assays were used. A subcutaneous transplanted UM tumor model was used in mice to verify the therapeutic effect. RESULTS: In UM, the expression level of HMOX1 was strongly correlated with the immune score and the infiltration level of various immune cells. ZnPP can inhibit the growth of UM cells, promote cell apoptosis, and block the cell cycle at G0/G1 phase in vitro. HO-1 knockout can effectively inhibit the proliferation of UM cells. ZnPP effectively inhibited the growth of UM and promoted the infiltration of CD8+ T cells in a subcutaneous tumor transplantation model. CONCLUSIONS: These results indicate that targeting HO-1 in UM has the potential for independent targeted immunotherapy or adjuvant immunotherapy.

Hou C, Wan Q, Xiao L, Xiao Q, Zhang M, Yan N, Investigative ophthalmology & visual science

Aug 1, 2024

Alternative localization of HEME OXYGENASE 1 in plant cells regulates cytosolic heme catabolism.

Heme, an organometallic tetrapyrrole, is widely engaged in oxygen transport, electron delivery, enzymatic reactions, and signal transduction. In plants, it is also involved in photomorphogenesis and photosynthesis. HEME OXYGENASE 1 (HO1) initiates the first committed step in heme catabolism, and it has generally been thought that this reaction takes place in chloroplasts. Here, we show that HO1 in both Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) has 2 transcription start sites (TSSs), producing long (HO1L) and short (HO1S) transcripts. Their products localize to the chloroplast and the cytosol, respectively. During early development or de-etiolation, the HO1L/HO1S ratio gradually increases. Light perception via phytochromes (Phys) and cryptochromes elevates the HO1L/HO1S ratio in the whole seedling through the functions of ELONGATED HYPOCOTYL 5 (HY5) and HY5 HOMOLOG and through the suppression of DE-ETIOLATED 1, CONSTITUTIVE PHOTOMORPHOGENESIS 1, and PHYTOCHROME INTERACTING FACTORs. HO1L introduction complements the HO1-deficient mutant; surprisingly, HO1S expression also restores the short hypocotyl phenotype and high pigment content and helps the mutant recover from the genomes uncoupled (gun) phenotype. This indicates the assembly of functional Phys within these lines. Furthermore, our findings support the hypothesis that a mobile heme signal is involved in retrograde signaling from the chloroplast. Altogether, our work clarifies the molecular mechanism of HO1 TSS regulation and highlights the presence of a cytosolic bypass for heme catabolism in plant cells.

Chen Y, Nishimura K, Tokizawa M, Yamamoto YY, Oka Y, Matsushita T, Hanada K, Shirai K, Mano S, Shimizu T, Masuda T, Plant physiology

Jul 28, 2024

Heme oxygenase 1 (HO1) regulates autophagy and apoptosis via the PI3K/AKT/mTOR signaling pathway of yak Sertoli cells.

Successful male reproduction depends on healthy testes. Autophagy has been confirmed to be active during many cellular events associated with the testes. It is not only crucial for testicular spermatogenesis but is also an essential regulatory mechanism for Sertoli cell (SCs) ectoplasmic specialization integrity and normal function of the blood-testis-barrier. Hypoxic stress induces oxidative damage, apoptosis, and autophagy, negatively affecting the male reproductive system. Cryptorchidism is a common condition associated with infertility. Recent studies have demonstrated that hypoxia-induced miRNAs and their transcription factors are highly expressed in the testicular tissue of infertile patients. Heme oxygenase 1 (HO1) is a heat-shock protein family member associated with cellular antioxidant defense and anti-apoptotic functions. The present study found that the HO1 mRNA and protein are up-regulated in yak cryptorchidism compared to normal testes. Next, we investigated the expression of HO1 in the SCs exposed to hypoxic stress and characterized the expression of key molecules involved in autophagy and apoptosis. The results showed that hypoxic stress induced the upregulation of autophagy of SCs. The down-regulation of HO1 using siRNA increases autophagy and decreases apoptosis, while the over-expression of HO1 attenuates autophagy and increases apoptosis. Furthermore, HO1 regulates autophagy and apoptosis via the PI3K/AKT/mTOR signaling pathway. These results will be helpful for further understanding the regulatory mechanisms of HO1 in yak cryptorchidism.

Yan Q, Wang Q, Nan J, Chen T, Wang J, Zhang Y, Yuan L, Theriogenology

May 1, 2024

Retraction: Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling.

The above article, published online on 16th October 2009 in Wiley Online Library (wileyonlinelibrary.com) and corrected in 2014 with a Corrigendum (JNeurochem 128(6): 975, URL: https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2011.07368.x) correcting Figure 3 of the original publication, has been retracted by agreement between the journal's Editor-in-Chief, Andrew Lawrence, the International Society for Neurochemistry and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised regarding possible image manipulation of Figure 5b. Corresponding author Alba Minelli as well as all other authors have been contacted to clarify their respective contribution to the article, and provide the original scanned films upon request for the editorial team's review. Corresponding author Alba Minelli confirmed the following author contributions in the corrected version (J Neurochem. 2014 Mar;128(6):975) as the final version of the published manuscript which all authors had read and approved: A. Minelli (contact): substantial contribution to conception and design, drafting the article, data interpretation, C .Conte: real-time PCR and gene silencing experiments, data acquisition and analysis, S. Grottelli: data acquisition and analysis, I. Bellezza: drafting the article, data acquisition and analysis, C. Emiliani: revising the article critically for important intellectual content, J. Bolaños: revising the article critically for important intellectual content. Since the original data could not be retrieved to dispel the new concerns regarding Figure 5 of the original publication, the journal no longer has confidence in the results and conclusions drawn. REFERENCE Minelli, A., Conte, C., Grottelli, S., Bellezza, I., Emiliani, C., & Bolaños, J. P. (2009). Cyclo(his-pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling. Journal of Neurochemistry, 111(4), 956-966. https://doi.org/10.1111/j.1471-4159.2009.06376.x.

GreenMedInfo, Journal of neurochemistry

Aug 1, 2023

Heme oxygenase 1 in erythropoiesis: an important regulator beyond catalyzing heme catabolism.

Heme oxygenase 1 (HO-1), encoded by the HMOX-1 gene, is the main heme oxygenase that catalyzes the degradation of heme into iron, carbon monoxide, and biliverdin. HMOX-1 gene expression is stimulated by oxidative stress and regulated at transcriptional and post-transcriptional levels. After translation, subcellular location and protein stability of HO-1 are also altered by different extracellular and intracellular stimuli. HO-1 plays a key role in regulating iron homeostasis and cell protection and has become a new target for disease treatment. Erythropoiesis is a tightly controlled, iron-dependent process that begins with hematopoietic stem cells and maturates to red blood cells. HO-1 is expressed in hematopoietic stem/progenitor cells, hematopoietic niche cells, erythroblasts, and especially erythroblastic island and phagocytic macrophages. HO-1 functions importantly in the entire erythroid development process by influencing hematopoietic stem cell proliferation, erythroid lineage engagement, terminal erythroid differentiation, and even senescent RBC erythrophagocytosis. HO-1 is also related to stress erythropoiesis and certain red blood cell diseases. Elucidation of HO-1 regulation and function in erythropoiesis will be of great significance for the treatment of related diseases.

Liu R, Zhang X, Nie L, Sun S, Liu J, Chen H, Annals of hematology

Jun 1, 2023