HIF‐1α forms regulatory loop with YAP to coordinate hypoxia‐induced adriamycin resistance in acute myeloid leukemia cells

Zhu, Bin; Pan, Shaoming; Liu, Juanjuan; Wang, Suli; Ni, Ying; Xiao, Linlin; Wei, Quhao; Peng, You; Ding, Zhiyong; Zhao, Wei‐Li

doi:10.1002/cbin.11246

Cited by 18 publications

(10 citation statements)

References 39 publications

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“…Generally, in the nucleus, YAP mainly relied on multiple domains to interact with transcription factors to form complexes, promoting the expression and activation of downstream target genes [11,20]. Bin Zhu et al reported that YAP sustained HIF-1α stability and promoted HIF-1α's activity on the target gene pyruvate kinase M2 (PKM2), thereby inducing chemoresistance in acute myeloidleukemia under hypoxia [30]. Recent study has demonstrated that HMGB1 triggered both YAP and HIF-1α nuclear translocation and enhanced YAP and HIF-1α interaction promoting pancreatic cancer stemness [19].…”

Section: Discussionmentioning

confidence: 99%

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression

Song¹,

Qiu²,

Wang³

et al. 2023

Int. J. Biol. Sci.

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Background:The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results:The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.

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Section: Discussionmentioning

confidence: 99%

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression

Song¹,

Qiu²,

Wang³

et al. 2023

Int. J. Biol. Sci.

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“…Overall, we conclude that cCr interferes with cell growth, inhibits cell cycle progression, and impairs chemotaxis/cell invasion likely through both its effects on cellular metabolism as well as microtubule dynamics. Of note, YAP expression has also been shown to correlate with HIF-dependent adriamycin (DOX) resistance in leukemia [100]. And, down-regulation of CKB in Skov3 ovarian cancer cells enhanced sensitivity to doxorubicin [72].…”

Section: Discussionmentioning

confidence: 99%

HIF-dependent CKB expression promotes breast cancer metastasis, whereas cyclocreatine therapy impairs cellular invasion and improves chemotherapy efficacy

Krutilina

Playa

Schwab

et al. 2021

Preprint

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The oxygen-responsive Hypoxia Inducible Factor (HIF)–1 promotes several steps of the metastatic cascade. A hypoxic gene signature is enriched in triple negative breast cancers (TNBCs), which correlates with poor patient survival. Since inhibiting the HIF transcription factors with small molecules is challenging, we sought to identify genes downstream of HIF-1 that could be targeted to block invasion and metastasis. Creatine kinase brain isoform (CKB) was identified as a highly differentially expressed gene in a screen of HIF-1 wild type and knockout mammary tumor cells derived from a transgenic model of metastatic breast cancer. CKB is a cytosolic enzyme that reversibly catalyzes the phosphorylation of creatine, generating phosphocreatine (PCr) in the forward reaction, and regenerating ATP in the reverse reaction. Creatine kinase activity is inhibited by the creatine analog cyclocreatine (cCr). Loss and gain of function genetic approaches were used in combination with cCr therapy to define the contribution of CKB expression or creatine kinase activity to cell proliferation, migration, invasion, and metastasis in ER-negative breast cancers. Although tumor cell-intrinsic CKB was not essential for breast tumor cell proliferation or cell migration in vitro, CKB was necessary for cell invasion in vitro and strongly promoted tumor growth and metastasis in vivo. Similarly, cyclocreatine therapy repressed cell migration, cell invasion, formation of invadopodia, and lung metastasis. Moreover, in common TNBC cell line models, the addition of cCr to conventional agents, paclitaxel (Taxol) or doxorubicin, was either additive or synergistic to repress tumor cell growth.

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“…For example, HIF-1αhigh-expression-mediated microenvironment hypoxia in MSC is one of the important triggers of the niches tumorous process (37). Hypoxia can not only enhance the adhesion and chemotaxis between LSC and MSC, but also reduce the sensitivity of LSC to chemotherapy drugs (39,40).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics-based Prediction of the mechanism and targets for BushenjieduDecoction in preventing relapse of acute leukemia

Sun

Feng-ying

Wei

et al. 2020

Preprint

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Background: Leukemia is a lethal myeloproliferative disorder, its’ relapse following chemotherapy is the major concern in clinical practice. For a long time, we found that traditional Chinese medicines such as Bushenjiedudecoction (BSJD) have significant effects on delaying relapse. However, the underlying mechanisms are not clear, which limits the clinical application of BSJD decoction. Methods: Therefore, we tried to make some explorations in this study. We isolated mesenchymal stem cells (MSC) after treated them with BSJD for proteomic analysis. And then 109 targets were screened out through analysis of the shared proteins of that affected by BSJD and those related to leukemia. Subsequently, the data were analyzed by GO functions, KEGG pathways, PPI network and topological analysis, and then some nodes were selected for animal experiment. Results: As a result, we demonstrated the effective targets of BSJD on MSC through bioinformatics analysis and explored the potential mechanism of BSJD from its influence on niches.These targets contains Hspb1、Dnmt1、Mmp2、Thbs1、Crebbp、Hmgb1、Acta2、Cdkn1b、Atg7、Tsc2 and Icam1. Afterwards, we confirmed BSJD reduced the gene expression of ICAM-1 through cultured MSC in vitro.Conclusions: We screened the potential targets of BSJD on MSC through proteomics and bioinformatics analysis, and selected some genes for experimental verification. These studies demonstrated the effect of BSJD on MSC. We hope that this research method could provide a new way of systematically studying the effects of traditional Chinese medicine on diseases.

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HIF‐1α forms regulatory loop with YAP to coordinate hypoxia‐induced adriamycin resistance in acute myeloid leukemia cells

Cited by 18 publications

References 39 publications

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression

HIF-dependent CKB expression promotes breast cancer metastasis, whereas cyclocreatine therapy impairs cellular invasion and improves chemotherapy efficacy

Bioinformatics-based Prediction of the mechanism and targets for BushenjieduDecoction in preventing relapse of acute leukemia

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