Hematopoietic Substrate-1-Associated Protein X-1 Regulates the Proliferation and Apoptosis of Endothelial Progenitor Cells Through Akt Pathway Modulation

Wang

J Cellular Molecular Medi

2021

HCLS1-associated protein X-1 (HAX1), an anti-apoptotic molecular, overexpresses in glioma. However, the role of HAX1 in glioma cell surviving in hypoxic environment remains unclear. Western blotting, qRT-PCR, Transwell assay, TUNEL assay, wounding healing assay, clone formation, tumour xenograft model and immunohistochemical staining were used to investigate the role of HAX1 in glioma. HAX1 regulated by HIF-1α was increased in glioma cells cultured in hypoxia. Silencing of HAX1 could cause an increased apoptosis of glioma cells cultured in hypoxia. Silencing of HAX1 also decreased the proliferation, migration and invasion of glioma cells cultured in hypoxia. Increased mitochondrial fission could prevent glioma cells from the damage induced by HAX1 knockdown in hypoxia. Furthermore, HAX1 was found to regulate glioma cells through phosphorylated AKT/Drp signal pathway. In conclusion, our study suggested that HAX1 promoted survival of glioma cells in hypoxic environment via AKT/Drp signal pathway. Our study also provided a potential therapeutic target for glioma.

Section: Discussionmentioning

confidence: 99%

“… 24 Importantly, recent studies reported that HAX1 was overexpressed in glioma and inhibits apoptosis of glioma. 25 , 26 , 27 However, the role of HAX1 in glioma cell cultured in hypoxia remains unclear.…”

Section: Introductionmentioning

confidence: 99%

HAX1 maintains the glioma progression in hypoxia through promoting mitochondrial fission

Wang

J Cellular Molecular Medi

2021

Cell Biology International

“…Previous study indicated that the apoptosis of EPCs could lead to thrombosis formation, platelet aggregation, and vasoconstriction, which are promoting factors of atherosclerosis (Wu et al, 2016). Bcl‐2 is a classical antiapoptotic factor, which could regulate the repair process of vascular endothelium through promoting proliferation of EPCs and inhibiting apoptosis (Guo et al, 2018; Li et al, 2017). Whether 14‐3‐3‐η could affect EPCs apoptosis and Bcl‐2 expression has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Functional damage of endothelial progenitor cells is attenuated by 14‐3‐3‐n through inhibition of mitochondrial injury and oxidative stress

Sun

Zhang

et al. 2020

Endothelial progenitor cells (EPCs) are precursor cells of vascular endothelial cells, which are widely involved in the pathological process of cardiovascular diseases. EPCs apoptosis could accelerate the process of cardiovascular diseases. 14-3-3-η protein has been proved to be a potent antiapoptosis molecule. However, inhibition of EPCs apoptosis by 14-3-3-η and further specific mechanism have not been investigated. EPCs were isolated from human cord blood, and identified using VEGFR2 and CD34. 14-3-3-η overexpression model in vitro was established. Cell invasion, apoptosis, and proliferation were measured by transwell, flow cytometry, and Cell Counting Kit-8, respectively. Expression of 14-3-3-η, Bcl-2, and voltagedependent anion channel 1 (VDAC1) were measured using quantitative real-time polymerase chain reaction and western blot analysis. Reactive oxygen species (ROS) intensity was measured using 2ʹ-7ʹ dichlorofluorescin diacetate probe. Mitochondrial membrane potential was detected using JC-1 dye. Overexpression of 14-3-3-η significantly promoted invasion and proliferation, but suppressed apoptosis of EPCs. Overexpression of 14-3-3-η remarkably inhibited ROS and promoted antioxidant enzyme levels in EPCs. 14-3-3-η might inhibit apoptosis of EPCs through attenuating mitochondrial injury. This study might provide a new target, 14-3-3-η, for the prevention and treatment of cardiovascular diseases through targeting EPCs.

Journal Cellular Physiology

“…HSP90, a chaperone protein, and HAX‐1 binding promotes the combination of HSP90 and AKT serine/threonine kinase 1 (Akt1), leading to the phosphorylation of Akt1 (Guo, Deng, & Wei, 2018). Association HAX‐1 with cIAP2, which is one of the ubiquitin E3 ligases, induces the homo‐dimerization and autoubiquitination of cIAP2, leading to subsequent activation of the noncanonical nuclear factor‐κB (NF‐κB) signaling pathway (Choi et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

HTLV‐1 viral oncoprotein HBZ contributes to the enhancement of HAX‐1 stability by impairing the ubiquitination pathway

Tanaka

Mukai

Ohshima

2020

Human T‐cell leukemia virus type 1 (HTLV‐1) is an oncogenic retrovirus that causes adult T‐cell leukemia (ATL). The viral protein HTLV‐1 basic leucine‐zipper factor (HBZ), which is constitutively expressed in all ATL patient cells, contributes toward the development of ATL; however, the underlying mechanism has not been elucidated yet. Here, we identified HS‐1‐associated protein X‐1 (HAX‐1) as a novel binding partner of HBZ. Interestingly, HAX‐1 specifically associated with HBZ‐US, but not HBZ‐SI, in the cytoplasm. HBZ suppressed the polyubiquitination levels of HAX‐1 protein by inhibiting the association HAX‐1 with F‐box protein 25 (FBXO25), which is a member of the SCF E3 ubiquitin ligase complex, and promoted the stabilization of HAX‐1 levels. In fact, the protein levels of HAX‐1 were significantly increased in HTLV‐1 infected and the overexpressing HBZ in uninfected T‐cell lines. Enhanced HAX‐1 correlated well to suppression of caspase 9 processing, suggesting that HBZ may contribute to the enhancement of antiapoptotic function for HAX‐1. Our results revealed a role for HBZ on HAX‐1 stabilization by abrogating the ubiquitination‐mediated degradation pathway, which may play an important role in understanding the potential mechanisms of HTLV‐1 related pathogenesis.