Yin-Yang-1 decreases Fas-induced apoptosis in acute lymphoblastic leukemia under hypoxic conditions: its implications in immune evasion

Martínez-Torres, Estefany; Lopez-Perez, Tania V.; Morales-Martinez, Mario; Huerta-Yépez, Sara

doi:10.24875/bmhim.20000187

Cited by 3 publications

(6 citation statements)

References 48 publications

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“…In addition, the FAS-FASL pathway is essential for the cytotoxicity of CTLs, including CAR-T cells, in the elimination of tumors in both tumor antigen-specific and antigen-independent manners [ 11 , 14 ]. To avoid FAS-mediated apoptosis, human cancer cells often down-regulate FAS expression and may use it as a mechanism to evade cell death to survive and progress [ 27 , 28 ]. For example, it was reported that FAS is highly expressed in normal human colon epithelial cells but is down-regulated in human colorectal carcinoma, whereas complete loss of FAS expression is often observed in metastatic human colorectal tumor [ 4 , 5 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo

Merting

Poschel

et al. 2022

Cancers

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A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas. Analysis of single-cell RNA-Seq datasets revealed that FAS is highly expressed in epithelial cells and immune cells but down-regulated in colon-tumor cells in human colorectal-cancer patients. Codon usage-optimized mouse and human FAS cDNA was designed, synthesized, and encapsulated into cationic lipid to formulate nanoparticle DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Overexpression of codon usage-optimized FAS in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro, suppressed colon tumor growth, and increased the survival of tumor-bearing mice in vivo. Overexpression of codon-optimized FAS-induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. DOTAP-Chol-mFAS therapy exhibited no significant liver toxicity. Our data determined that tumor-selective delivery of FAS DNA nanoparticles is sufficient for suppression of human colon tumor growth in vivo.

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Section: Introductionmentioning

confidence: 99%

Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo

Merting

Poschel

et al. 2022

Cancers

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“…Moreover, a bioinformatics analysis revealed that patients with high levels of HIF-1α also express high levels of YY1 and low levels of Fas. These results suggest that YY1 negatively regulates the expression of the Fas receptor, which would be involved in the escape of leukemic cell from the immune response is another mechanism to contributing to the ALL pathogenesis [29]. Once we demonstrated that HIF-1α positively regulates the expression of YY1, we then evaluated the effect of using a chemical inhibitor of HIF-1α activated activity.…”

Section: Discussionmentioning

confidence: 95%

“…Nevertheless, the role of these transcription factors in the pathogenesis of ALL is not clear and given their possible coexpression and correlation with poor prognosis, it is plausible to think that there is a relationship between these two transcription factors. Our first approach hypothesized that HIF-1α could regulate transcriptionally the expression of YY1 since we previously showed that HIF-1α and YY1 increase their expression under hypoxic conditions [29]. Understanding the regulatory mechanism underlying YY1 expression and its implications in ALL, as well as its relationship with the transcription factor HIF-1α, is important for diagnostic and prognostic purposes.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Regulation of Yin-Yang 1 Expression through the Hypoxia Inducible Factor-1 in Pediatric Acute Lymphoblastic Leukemia

Antonio‐Andres

Martínez-Ruiz

Morales-Martinez

et al. 2022

IJMS

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Yin-Yang transcription factor 1 (YY1) is involved in tumor progression, metastasis and has been shown to be elevated in different cancers, including leukemia. The regulatory mechanism underlying YY1 expression in leukemia is still not understood. Bioinformatics analysis reveal three Hypoxia-inducible factor 1-alpha (HIF-1α) putative binding sites in the YY1 promoter region. The regulation of YY1 by HIF-1α in leukemia was analyzed. Mutation of the putative YY1 binding sites in a reporter system containing the HIF-1α promoter region and CHIP analysis confirmed that these sites are important for YY1 regulation. Leukemia cell lines showed that both proteins HIF-1α and YY1 are co-expressed under hypoxia. In addition, the expression of mRNA of YY1 was increased after 3 h of hypoxia conditions and affect several target genes expression. In contrast, chemical inhibition of HIF-1α induces downregulation of YY1 and sensitizes cells to chemotherapeutic drugs. The clinical implications of HIF-1α in the regulation of YY1 were investigated by evaluation of expression of HIF-1α and YY1 in 108 peripheral blood samples and by RT-PCR in 46 bone marrow samples of patients with pediatric acute lymphoblastic leukemia (ALL). We found that the expression of HIF-1α positively correlates with YY1 expression in those patients. This is consistent with bioinformatic analyses of several databases. Our findings demonstrate for the first time that YY1 can be transcriptionally regulated by HIF-1α, and a correlation between HIF-1α expression and YY1 was found in ALL clinical samples. Hence, HIF-1α and YY1 may be possible therapeutic target and/or biomarkers of ALL.

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“…With receiving more and more attention, an increasing number of key proteins have been identified in ALL 8–11 . PAQR3 has been uncovered to be a critical regulator into various cancers 15–18 .…”

Section: Discussionmentioning

confidence: 99%

“…More and more evidence illustrated that alterations in genes can affect the malignant behaviors of ALL cells. For example, Yin‐Yang‐1 retards cell apoptosis induced by Fas in ALL under hypoxic conditions 8 . Additionally, SOCS3 methylation regulated JAK/STAT pathway to affect the progression of pediatric ALL 9 .…”

Section: Introductionmentioning

confidence: 99%

PAQR3 inhibits proliferation and aggravates ferroptosis in acute lymphoblastic leukemia through modulation Nrf2 stability

Jin

Tong

2021

Immunity Inflam & Disease

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Introduction Acute lymphoblastic leukemia (ALL) is a usual hematological tumor, which was featured by malignant proliferation of lymphoid progenitor cells. Many important factors participate into the regulation of ALL, including proteins. PAQR3 (also named RKTG) has been proved to take part in many human cancers by acting as a tumor suppressor. PAQR3 has bee n shown to repress human leukemia cells proliferation and induce cell apoptosis, but its role and relevant regulatory mechanism on cell proliferation and ferroptosis in ALL needs more exploration. Methods The genes expression was detected through quantitative reverse transcription polymerase chain reaction (mRNA) or western blot (protein). The cell proliferation was assessed through Cell Counting Kit‐8 and 5‐ethynyl‐2‐deoxyuridine assays. The levels of MDA, DCF, and intracellular free Fe in ALL cells were tested through the commercial kits. The cell apoptosis was determined through flow cytometry analysis. The binding ability of PAQR3 and nuclear factor erythroid 2‐related factor 2 (Nrf2) was verified through pull down assay. Results PAQR3 expression was firstly assessed in ALL patients and cell lines, and discovered to be downregulated. It was verified that PAQR3 suppressed ALL cells proliferation. Further experiments proved that PAQR3 aggravates ferroptosis in ALL. In addition, AQR3 bound with Nrf2, and modulated its expression through ubiquitination in ALL. Finally, through rescue assays, it was demonstrated that Nrf2 overexpression reversed the effects of PAQR3 on cell proliferation and ferroptosis. Conclusion Findings from our work uncovered that PAQR3 inhibited proliferation and aggravated ferroptosis in ALL through modulation Nrf2 stability. This study suggested that PAQR3 may serve as an effective biological marker for ALL treatment.

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Yin-Yang-1 decreases Fas-induced apoptosis in acute lymphoblastic leukemia under hypoxic conditions: its implications in immune evasion

Cited by 3 publications

References 48 publications

Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo

Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo

Transcriptional Regulation of Yin-Yang 1 Expression through the Hypoxia Inducible Factor-1 in Pediatric Acute Lymphoblastic Leukemia

PAQR3 inhibits proliferation and aggravates ferroptosis in acute lymphoblastic leukemia through modulation Nrf2 stability

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