HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells

Abstract

HACE1, an E3 ubiquitin-protein ligase, is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer. However, its role in glioma remains elusive. Here, we observed increased expression of HACE1 in gliomas related to control subjects, and found a strong correlation of high HACE1 expression with poor prognosis in patients with WHO grade III and IV as well as low-grade glioma (LGG) patients receiving radiotherapy. HACE1 knockdown obviously suppressed malignant behaviors of glioma cells, while ectopic expression of HACE1 enhanced cell growth in vitro and in vivo. Further studies revealed that HACE1 enhanced protein stability of nuclear factor erythroid 2-related factor 2 (NRF2) by competitively binding to NRF2 with another E3 ligase KEAP1. Besides, HACE1 also promoted internal ribosome entry site (IRES)-mediated mRNA translation of NRF2. These effects did not depend on its E3 ligase activity. Finally, we demonstrated that HACE1 dramatically reduced cellular ROS levels by activating NRF2, thereby decreasing the response of glioma cells to radiation. Altogether, our data demonstrate that HACE1 causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells by activating NRF2, and indicate that it may act as the role of prognostic factor and potential therapeutic target in glioma.

Knockdown of Nrf2 radiosensitizes glioma cells by inducing redox stress and apoptosis in hypoxia

“…A further study indicated that ionizing radiation activated ARE-dependent transcription in breast cancer cells, and the Nrf2-ARE pathway was important in maintaining resistance to irradiation under specific circumstances (30). Moreover, it was preliminarily shown that Nrf2 might enhance the resistivity to radiotherapy of specific human malignant cells including glioma (31)(32)(33). These findings led to the hypothesis that the antioxidant role of Nrf2 would be very important in the radioresistance of glioma cells.…”

Ubiquitin-modifying enzymes in Huntington’s disease

“…Colocalization studies suggest an interaction between HTT IBs and HIP2 in SH-SY5Y cells and post-mortem brain tissue, indicating that HIP2 colocalizes with HTT (de Pril et al, 2007). While knockdown of the HIP2 protein or deletion of its catalytic domain reduced mHTT IBs and polyQ-induced cell death in SH-Sy5Y cells, overexpression of HIP2 did not affect mHTT aggregation (de Pril et al, 2007), suggesting that HIP2 is not a limiting factor in controlling mHTT aggregation. Strikingly, knockdown of HIP2 in patient-derived induced pluripotent stem cells (iPSCs) had no effect on the number of mHTT IBs (Koyuncu et al, 2018).…”

“…HACE1 is highly expressed in neuronal and glial cells and is involved in Golgi membrane fusion, the regulation of small GTPases, and protein degradation. Furthermore, HACE1 promotes the stability NRF2 (Da et al, 2021), which is an important regulator of the antioxidative stress response (Ma, 2013). Rotblat and colleagues found that HACE1 is reduced in the striatum of HD patients.…”

Scavenging ROS to Alleviate Acute Liver Injury by ZnO‐NiO@COOH

“…[50] In addition, ROS can activate the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element signaling pathway, in which mitogen-activated protein kinases, protein kinase C, and phosphatidyl alcohol-3-kinase participate in several protein kinase pathways. [52,53] In-depth mechanism exploration still needs more experiments to verify. Although the results of this study partially revealed the mechanisms underlying the ability of ZnO 0.2 -NiO@COOH to absorb ROS, the specific pathways remain unclear, thus further studies are warranted.…”