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Breast cancer (BC) is one of the most frequently diagnosed malignant tumors worldwide. Period circadian protein homolog 1 (PER1) is a primary component of the biorhythm molecular oscillation system. The objective of this study was to elucidate the association between PER1 and clinical BC outcomes and determine the potential effect of PER1 on BC tumor development. Immunohistochemical staining for PER1 was performed on 30 normal breast tissue and 172 BC samples. Those BC cases were categorized into two groups to analyze the prognostic significance of PER1 expression. The expression of key proteins in the MEK/ERK pathway (ERK1/2, ERK5, P38, JNK1/2/3) and their phosphorylation levels (p-ERK1/2, p-ERK5, p-P38, and p-JNK1/2/3) were elucidated by western blot test. XMD17-109, a specific ERK5 inhibitor, was used to treat BT-549 and MCF-7 BC cells with knockdown of PER1. Increased PER1 expression was identified in 26 and 80 normal breast and BC tissues, respectively, whereas low expression was detected in 4 normal and 92 BC tissues. Although no differences were observed in the estrogen receptor (ER), menstrual cycle, TNM, progesterone receptor (PR), and HER-2 stages, age, and tumor size between the two cohorts, both the rate of axillary lymph node metastasis ( <0.05) and vascular tumor thrombosis ( <0.05) were enhanced in the low cohort. Furthermore, the low-PER1 group had the worst overall survival (HR: 0.44, 95% CI: 0.20-0.96, =0.035) and relapse-free survival (HR: 0.29, 95% CI: 0.13-0.67, =0.002). PER1 overexpression reduced phosphorylation levels of ERK5 in Lenti-blast-PER1-MDA-MB-231 BC cells ( <0.05), while PER1 silencing had the opposite effect on the pGenesil-1-PER1-MCF-7 cells ( <0.05). Colony formation, 5-ethynyl-2'-deoxyuridine, and Transwell cell migration and invasion assays revealed that XMD17-109 antagonized the enhancement of cell proliferate, migration, and invasion by PER1 knockdown ( <0.05). PER1 plays an anti-tumor role by regulating the MEK5/ERK5 pathway in BC.

Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.

Extracellular signal-regulated kinase 5 (ERK5) belongs to the mitogen-activated protein kinase (MAPK) family that consists of highly conserved enzymes expressed in all eukaryotic cells and elicits several biological responses, including cell survival, proliferation, migration, and differentiation. In recent years, accumulating lines of evidence point to a relevant role of ERK5 in the onset and progression of several types of cancer. In particular, it has been reported that ERK5 is a key signaling molecule involved in almost all the biological features of cancer cells so that its targeting is emerging as a promising strategy to suppress tumor growth and spreading. Based on that, in this review, we pinpoint the hallmark-specific role of ERK5 in cancer in order to identify biological features that will potentially benefit from ERK5 targeting.

Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.

Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.

Psoriasis is a chronic inflammatory skin disease, often accompanied by increased infiltration of immune cells, especially neutrophils. However, the detailed mechanism of the neutrophil function in psoriasis progression remains unclear. Here, we found that both Src homology‐2 domain‐containing protein tyrosine phosphatase‐2 (SHP2) and neutrophils were highly correlated to developing psoriasis by single‐cell ribonucleic acid (RNA) sequencing and experiment verification. The deficiency of SHP2 in neutrophils significantly alleviated psoriasis‐like phenotype in an imiquimod‐induced murine model. Interestingly, high levels of neutrophil extracellular traps (NETs) were produced in the inflamed lesions of psoriatic patients. In addition, imiquimod‐induced psoriasis‐like symptoms were remarkably ameliorated in peptidyl arginine deiminase 4 (PAD4) knockout mice, which cannot form NETs. Mechanistically, RNA‐seq analysis revealed that SHP2 promoted the formation of NETs in neutrophils via the ERK5 pathway. Functionally, this mechanism resulted in the infiltration of pro‐inflammatory cytokines such as TNF‐α, IL‐1β, IL‐6, IL‐17A, and CXCL‐15, which enhances the inflammatory response in skin lesions and reinforces the cross‐talk between neutrophils and keratinocytes, ultimately aggravating psoriasis. Our findings uncover a role for SHP2 in NET release and subsequent cell death known as NETosis in the progression of psoriasis and suggest that SHP2 may be a promising therapeutic target for psoriasis. Single‐cell RNA sequencing and experimental verification were combined to announce that SHP2 aggravates psoriasis‐like skin inflammation in mice via ERK5‐dependent NETosis. During this process, inflammatory cytokines: TNF‐α, IL‐1β, IL‐6, IL‐17a, and CXCL‐15 were infiltrated in skin and contributed to psoriasis. Our study provides evidence for the role of SHP2 in NETosis and psoriasis. SHP2 may be a potential therapeutic target for the treatment of psoriasis.

The intestine of zebrafish consists of mucosa, muscularis and serosa. Intestinal epithelial cells (IECs) act as a physical and biochemical barrier to protect against invasion by external commensal bacteria. Cell junction is one of the crucial basis of the barrier function. When cell junctions were disrupted, intestinal permeability would be naturally impeded. Extracellular signal-regulated kinase 5 (ERK5), belonging to the Mitogen-activated protein kinase (MAPK) family, is involved in the normal physiological development of the cardiovascular system and nervous system. But the role of erk5 in intestinal morphogenesis and intestinal function is yet to know. Here, we showed that knockout of the erk5 in zebrafish larvae resulted in intestinal wall hypoplasia, including the thinned intestinal wall, reduced intestinal folds, and disrupted cell junctions. In addition, the intestinal permeability assay demonstrated that knockout of erk5 resulted in increased intestinal permeability. All of these showed that erk5 plays an essential role in the maintenance of intestinal barrier function. Thus, our data indicate that erk5 is a critical effector in intestinal morphogenesis and intestinal function, and dysfunction of erk5 would lead to intestinal diseases.

The ERK5 signaling pathway has recently emerged as a critical regulator of soft tissue sarcoma (STS) biology, contributing to tumor initiation, progression, and maintenance. In this study, we identify VCAN, a chondroitin sulfate proteoglycan, as a novel transcriptional target of ERK5 and a central mediator of ERK5-related oncogenesis. Through a combination of genetic (silencing, overexpression) and pharmacological approaches, applied in both a chemically induced murine sarcoma model and several human STS cell lines, we demonstrate that ERK5 positively regulates VCAN expression. Functionally, VCAN silencing (by shRNAs) recapitulates the phenotypes of ERK5 silencing, including impaired migration, adhesion, proliferation, and tumorigenesis. Conversely, VCAN overexpression rescues these effects, confirming its essential role in ERK5-mediated oncogenesis. Furthermore, transcriptomic profiling reveals that VCAN accounts for a substantial portion of ERK5-regulated gene expression program. Analyses of human STS patient samples reveal significantly elevated mRNA levels of both VCAN and ERK5 compared to normal tissues. Notably, a strong correlation between VCAN and ERK5 expression, both at mRNA and protein levels, emerged in biopsies from leiomyosarcomas and undifferentiated pleomorphic sarcomas. Together, these findings uncover VCAN as a key effector in ERK5-driven tumorigenesis and highlight the ERK5/VCAN signaling axis as a promising therapeutic target in soft tissue sarcomas.

Nav1.8, a tetrodotoxin-resistant voltage-gated sodium channels (VGSCs) subtype encoded by SCN10A , which plays an important role in the production and transmission of peripheral neuropathic pain signals. Studies have shown that VGSCs may be key targets of MicroRNAs (miRNAs) in the regulation of neuropathic pain. In our study, bioinformatics analysis showed that the targeting relationship between miR-3584-5p and Nav1.8 was the most closely. The purpose of this study was to investigate the roles of miR-3584-5p and Nav1.8 in neuropathic pain. The effects of miR-3584-5p on chronic constriction injury (CCI)-induced neuropathic pain in rats was investigated by intrathecal injection of miR-3584-5p agomir (an agonist, 20 μM, 15 μL) or antagomir (an antagonist, 20 μM, 15 μL). The results showed that over-expression of miR-3584-5p aggravated neuronal injury by hematoxylin–eosin (H&E) staining and mechanical/thermal hypersensitivity in CCI rats. MiR-3584-5p indirectly inhibited the expression of Nav1.8 by up-regulating the expression of key proteins in the ERK5/CREB signaling pathway, and also inhibited the current density of the Nav1.8 channel, changed its channel dynamics characteristic, thereby accelerating the transmission of pain signals, and further aggravating pain. Similarly, in PC12 and SH-SY5Y cell cultures, miR-3584-5p increased the level of reactive oxygen species (ROS) and inhibited mitochondrial membrane potential (Δψm) in the mitochondrial pathway, decreased the ratio of apoptosis-related factor Bcl-2/Bax, and thus promoted neuronal apoptosis. In brief, over-expression of miR-3584-5p aggravates neuropathic pain by directly inhibiting the current density of Nav1.8 channel and altering its channel dynamics, or indirectly inhibiting Nav1.8 expression through ERK5/CREB pathway, and promoting apoptosis through mitochondrial pathway.

The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, β, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic β-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.