NFAT5 Regulated by STUB1, Facilitates Malignant Cell Survival and p38 MAPK Activation by Upregulating AQP5 in Chronic Lymphocytic Leukemia

Chen, Bei Li; Li, Yuchuan; Xu, Shujuan; Nie, Yuwei; Zhang, Jiang

doi:10.1007/s10528-021-10040-3

Cited by 9 publications

(7 citation statements)

References 31 publications

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“…NFAT5, the only known osmotically regulated transcription factor in mammals, [10] was found to be highly expressed in many types of leukemia ( Figure S4A ). Chen [11] reported that NFAT5 may be a therapeutic target in leukemia. Moreover, it has been reported that NFAT activation can be inhibited by black raspberry extracts (anthocyanins and flavonoids) [13] and that antioxidants can suppress the expression of NFAT5 [12] .…”

Section: Resultsmentioning

confidence: 99%

“…[10] In addition, NFAT5 has been reported to be a therapeutic target for leukemia. [11] Furthermore, antioxidants can effectively act on the expression of the NFAT5 protein. [12,13] Therefore, we speculated that NFAT5 may be a potential target of PSPAs.…”

Section: Introductionmentioning

confidence: 99%

“…NAFT5, also known as TonEBP/OREBP, which belongs to the NFAT family, is highly sensitive to hypertonicity [10] . In addition, NFAT5 has been reported to be a therapeutic target for leukemia [11] . Furthermore, antioxidants can effectively act on the expression of the NFAT5 protein [12,13] .…”

Section: Introductionmentioning

confidence: 99%

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Calcicoptosis Induced by Purple Sweet Potato Anthocyanins through the Nonosmotic Regulation of the NFAT5/S100A4‐S100A9 Pathway in Acute Lymphoblastic Leukemia

Guo

Jin

You

et al. 2022

Chemistry & Biodiversity

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Purple sweet potato is considered an abundant, inexpensive, and ideal source of anthocyanins. Purple sweet potato anthocyanins (PSPAs) have been shown to possess high antimutagenicity and antitumor effects due to the abundance of acylated anthocyanins. However, the effect and underlying mechanism of PSPA effects in acute lymphoblastic leukemia (ALL), especially T-cell acute lymphoblastic leukemia (T-ALL), remain unclear. In this study, the antileukemic effects of PSPAs and the underlying molecular mechanisms were evaluated by in vitro and in silico assays. PSPAs extracted from ten cultivars were analyzed and quantified. Anthocyanins from Nanzi 018, which showed the best antileukemic effect, were selected to analyze the underlying mechanism. First, the PSPAs potently reduced cell viability and induced apoptosis. Additionally, the PSPAs sharply increased intracellular Ca 2 + levels, which resulted in calcium overload in T-ALL cells. Furthermore, on the basis of bioinformatics analyses, we focused on an osmotically regulated transcription factor, NFAT5. Molecular docking preliminarily indicated that PSPA molecules bound and interacted with the NFAT5 protein. Western blot analyses confirmed that PSPAs elicited calcium overload by nonosmotic regulation of NFAT5/S100A4-S100A9 pathway activation. Moreover, pretreatment with a NFAT5 inducer confirmed that PSPAs targeted NFAT5 and affected p38/NF-кB/Bcl-2/Caspase-3 axis activation. This study demonstrates that PSPAs exert their antileukemic effects through calcicoptosis induction by targeting NFAT5.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Calcicoptosis Induced by Purple Sweet Potato Anthocyanins through the Nonosmotic Regulation of the NFAT5/S100A4‐S100A9 Pathway in Acute Lymphoblastic Leukemia

Guo

Jin

You

et al. 2022

Chemistry & Biodiversity

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“…After reviewing the literature, it was determined that NFAT5 has similar functions to TERT and plays an important role in various activities, such as immune regulation, metabolic regulation, DNA damage repair and tumorigenesis [43][44][45], such as non-small-cell lung cancer [46], pancreatic cancer [47], chronic lymphocytic leukemia [48] and melanoma [49]. It plays an important role in the occurrence and development of various human tumor diseases, and studies have shown that NFAT5 can regulate the transcription of the mouse TERT gene and promote the expression of TERT [50].…”

Section: Discussionmentioning

confidence: 99%

The expression level of chicken telomerase reverse transcriptase in tumors induced by ALV-J is positively correlated with methylation and mutation of its promoter region

Xiang

Chen

et al. 2022

Vet Res

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Avian leukosis virus subgroup J (ALV-J) can cause neoplastic diseases in poultry and is still widely prevalent in China. Chicken telomerase reverse transcriptase (chTERT) is the core component of telomerase, which is closely related to the occurrence and development of tumors. Our previous studies showed that chTERT is overexpressed in ALV-J tumors, but the mechanism is still not completely clear. Therefore, this study aims to analyze the possible molecular mechanism of chTERT overexpression in ALV-J tumors from the perspective of DNA methylation and promoter mutation. Methylation sequencing of the chTERT amplicon showed that ALV-J replication promoted the methylation level of the chTERT promoter. And the methylation level of the chTERT promoter in ALV-J tumors was significantly higher than that in tumor-adjacent and normal tissues. Compared with the tumor-adjacent and normal tissues, the chTERT promoter in each ALV-J tumors tested had a mutation of −183 bp C > T, and 36.0% (9/25) of the tumors also had mutations of −184 bp T > C, −73 bp::GGCCC and −56 bp A > T in the chTERT promoter, which formed the binding sites for the transcription factors NFAT5, TFAP2A and ZEB1, respectively. The results of RT–qPCR and Western blotting showed that the occurrence of these mutations significantly increased the expression level of chTERT. In conclusion, this study demonstrated that the high expression of chTERT in ALV-J tumors is positively correlated with the level of hypermethylation and mutation in its promoter, which provides a new perspective for further research on the molecular mechanism of chTERT in ALV-J tumorigenesis.

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“…They also demonstrated STUB1 connected to NFAT5 and stimulated its destruction. These data suggest the participation of AQP5 and NFAT5 in CLL diffusion and propose that AQP5 and NFAT5 could operate as a hopeful therapeutic target for CLL therapy [ 131 ].…”

Section: Aqps and Lymphoproliferative Diseasesmentioning

confidence: 99%

Critical Role of Aquaporins in Cancer: Focus on Hematological Malignancies

Allegra

Cicero

Mirabile

et al. 2022

Cancers

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Aquaporins are transmembrane molecules regulating the transfer of water and other compounds such as ions, glycerol, urea, and hydrogen peroxide. Their alteration has been reported in several conditions such as cancer. Tumor progression might be enhanced by aquaporins in modifying tumor angiogenesis, cell volume adaptation, proteases activity, cell–matrix adhesions, actin cytoskeleton, epithelial–mesenchymal transitions, and acting on several signaling pathways facilitating cancer progression. Close connections have also been identified between the aquaporins and hematological malignancies. However, it is difficult to identify a unique action exerted by aquaporins in different hemopathies, and each aquaporin has specific effects that vary according to the class of aquaporin examined and to the different neoplastic cells. However, the expression of aquaporins is altered in cell cultures and in patients with acute and chronic myeloid leukemia, in lymphoproliferative diseases and in multiple myeloma, and the different expression of aquaporins seems to be able to influence the efficacy of treatment and could have a prognostic significance, as greater expression of aquaporins is correlated to improved overall survival in leukemia patients. Finally, we assessed the possibility that modifying the aquaporin expression using aquaporin-targeting regulators, specific monoclonal antibodies, and even aquaporin gene transfer could represent an effective therapy of hematological malignancies.

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NFAT5 Regulated by STUB1, Facilitates Malignant Cell Survival and p38 MAPK Activation by Upregulating AQP5 in Chronic Lymphocytic Leukemia

Cited by 9 publications

References 31 publications

Calcicoptosis Induced by Purple Sweet Potato Anthocyanins through the Nonosmotic Regulation of the NFAT5/S100A4‐S100A9 Pathway in Acute Lymphoblastic Leukemia

Calcicoptosis Induced by Purple Sweet Potato Anthocyanins through the Nonosmotic Regulation of the NFAT5/S100A4‐S100A9 Pathway in Acute Lymphoblastic Leukemia

The expression level of chicken telomerase reverse transcriptase in tumors induced by ALV-J is positively correlated with methylation and mutation of its promoter region

Critical Role of Aquaporins in Cancer: Focus on Hematological Malignancies

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