Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma

Abstract

The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4. Consistent with a substrate relationship, Fxr1 is overexpressed in Fbxo4 knockout cells, tissues and in human cancer cells, harbouring inactivating Fbxo4 mutations. Critically, in head and neck squamous cell carcinoma, Fxr1 overexpression correlates with reduced Fbxo4 levels in the absence of mutations or loss of mRNA, suggesting the potential for feedback regulation. Direct analysis reveals that Fbxo4 translation is attenuated by Fxr1, indicating the existence of a feedback loop that contributes to Fxr1 overexpression and the loss of Fbxo4. Ultimately, the consequence of Fxr1 overexpression is the bypass of senescence and neoplastic progression.

Fxr1 regulates sleep and synaptic homeostasis

“…Homeostatic regulation of synaptic strength engages both cell autonomous and global levels mechanisms. Here we show that the insomnia GWAS-associated gene Based on our findings, we propose that during sleep deprivation and upscaling, Fxr1 protein level decreases due to its negative regulation by Gsk3β 18,19 . The decrease in Fxr1 protein induces broad alterations in synapse organization and metabolism, which subsequently result in an increase of synaptic GluA1 and postsynaptic excitatory activity.…”

“…3e The mechanisms by which Fxr1 is engaged both by SD and upscaling necessitate Gsk3 activity and a downregulation of Fxr1protein levels. Fxr1 has been shown to be phosphorylated by Gsk3 and targeted for degradation following it ubiquitination 18,19 . However, this regulation involves the priming of Fxr1 by other kinases and may thus integrate information from several upstream signaling pathways 18 .…”

“…Variants of the FXR1 locus are GWAS-identified risk factors for insomnia 16 and a schizophrenia-associated FXR1 variant is linked to sleep duration 17 . Interestingly, Fxr1 protein degradation is also regulated by Glycogen synthase kinase 3 beta (Gsk3) 18,19 and its brain expression is increased in response to lithium, a pharmacological agent inhibiting Gsk3 that is used for sleep regulation and the treatment of psychiatric disorders characterized by sleep disturbances, such as bipolar disorder 20,21 .…”

Molecular prognosticators in clinically and pathologically distinct cohorts of head and neck squamous cell carcinoma—A meta-analysis approach

“…(with prognostic efficacy), all of which were previously identified to play a major role in head and neck oncogenesis as well as in other cancers [45][46][47][48][49][50][51][52] EPS8, identified in ECS-laryngopharyngeal patients in this study, is known to be involved in the proliferation apoptosis, adhesion and migration in other cancers including HNSCC [53][54][55][56]. The correlation of these markers with the clinically/pathologically classified sub-cohorts (ALI+/PNI+) indicated their possible relevance as predictive panel, with a subset of genes providing survival impact.…”

Mental Illnesses-Associated Fxr1 and Its Negative Regulator Gsk3β Are Modulators of Anxiety and Glutamatergic Neurotransmission

“…Interaction between polymorphisms affecting cortical expression of the FXR1 and GSK3B genes have been shown to regulate mood-related behavioral dimensions in healthy humans and patients with bipolar disorder ( Del’Guidice et al, 2015 ; Bureau et al, 2017 ). This genetic interaction may be explained by the negative regulation of Fxr1 following its phosphorylation by Gsk3β ( Del’Guidice et al, 2015 ; Qie et al, 2017 ). Results presented here demonstrate how neuronal activity and related behavior are impacted by Gsk3β and Fxr1.…”