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Recent Research Progress
E3 ubiquitin-protein ligase 1 (HACE1) is a homologue to the E6-AP carboxyl terminus (HECT) family E3 ligase that binds to and ubiquitylates the GTP-bound active form of Ras-related C3 botulinum toxin substrate 1 (Rac1), a Rho family GTPase. HACE1 is ubiquitously expressed with relatively higher expression in heart, placenta, kidney, and brain. Ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) is a tumor suppressor that is inactivated in human Wilm’s tumor and other cancers.
Some works proved that HACE1 expression is reduced in breast tumors. Loss of HACE1 expression is commonly seen in clinical breast cancer data sets. HACE1 downregulation in normal human mammary epithelial cells (HMECs) results in the accumulation of the activated GTP-bound Ras-related C3 botulinum toxin substrate 1 (Rac1) partially transforming these cells. Molecular characterization of HACE1 in breast cancer shows that HACE1 expression attenuates Rac signaling in mammary epithelial cells resulting in diminishing breast cancer cell lines clonogenic potential, and that loss of HACE1 results in enhanced Rac signaling resulting in tumorigenicity. Although the knockdown of HACE1 or overexpression of human epidermal growth factor receptor-2 (HER2) alone in HMECs is not sufficient for tumorigenesis, HACE1 downregulation combined with HER2 overexpression fully transforms HMECs resulting in robust tumor formation. The reason is that overexpression of HER2 activates Rac1, which further accumulates upon HACE1 loss resulting in Rac1 hyperactivation. Notably, HACE1 was underexpressed or underwent allelic loss in cancer compared with respective normal tissues in glioblastoma, melanoma, lymphoma, lung and pancreatic cancers. Taken together, these data show that HACE1 is significantly decreased during the transformation from the normal to malignant state in breast cancer as well as other many other types of cancers.
Figure 1. Schematic overview of HACE1 loss in breast cancer (ET Goka, et al. 2015).
Some researchers provide evidence that HACE1 mutations underlie a new autosomal recessive neurodevelopmental disorder. HACE1 also interacts with members of the targeting GTPase (Rab) small GTPase subfamily. Rab1 appears to recruit HACE1 to the Golgi, where it plays a role in disassembly of the complex in mitosis. HACE1 is also reported to promote the recycling of the β2-adrenergic receptor (β2-AR) through a Rab11a-dependent mechanism. Zhao et al. reported an E3-ligase independent interaction through which HACE1 represses the transcriptional activity of retinoic acid receptors phosphorylation-deficient retinoic acid receptor α1 (RARα1), phosphorylation-deficient retinoic acid receptor β (RARβ) isoforms 1, 2 and 3; HACE1 thereby also represses the RAR-regulated genes cellular retinoic acid binding protein II (CRABPII), retinoid-inducible gene 1 (RIG1) and phosphorylation-deficient retinoic acid receptor β2 (RARβ2).
Many reports show that HACE1 is increased in the serum of patients with heart failure. And a finding that HACE1 has a protective function in the heart in response to haemodynamic stress suggests that HACE1 may be a potential diagnostic and therapeutic target for heart disease. Some experiment indicate that hearts from Hace1 - / - mice display abnormal cardiac hypertrophy, left ventricular dysfunction, accumulate microtubule-associated protein 1 light chain 3 (LC3) and ubiquitinated proteins, indicating impaired autophagy. Some data suggest that HACE1 mediates p62-dependent selective autophagic turnover of ubiquitinated proteins by its ankyrin repeat domain through protein-protein interaction. The robust induction of HACE1 expression in the heart under pathological stress conditions suggests that HACE1 participates in stress-induced cardiac hypertrophic remodelling.
Strikingly, some studys found a reduction of HACE1 levels in the striatum of Huntington disease patients, implicating HACE1 in the pathology of Huntington disease. HACE1 was found to be essential for optimal nuclear factor erythroid 2-related factor 2 (NRF2) activation in cells challenged with oxidative stress, as HACE1 depletion resulted in reduced NRF2 activity, stability, and protein synthesis, leading to lower tolerance against oxidative stress triggers. That is HACE1 protects against oxidative stress by promoting NRF2. NRF2 is a master regulator of the cellular antioxidative stress response and deregulated in both cancer and neurodegeneration. Moreover, ectopic expression of HACE1 in striatal neuronal progenitor cells provided protection against mutant Huntingtin-induced redox imbalance and hypersensitivity to oxidative stress, by augmenting NRF2 functions. Some results provide compelling evidence that HACE1 protects neuronal progenitor cells from mutant Huntingtin (mHTT) -induced oxidative stress by promoting NRF2 activity and the antioxidant response. Together, many findings suggest that low HACE1 expression may contribute to reduced expression and/or induction of NRF2 targets in HD striatum, and therefore to deficits in the oxidative stress response and selective vulnerability of striatal cells to mHTT-induced toxicity.