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Although melanoma therapy is improved by novel molecular targeted reagents, including vemurafenib, aberrant proliferation and early metastasis remain obstacles for melanoma; therefore, novel target molecules for melanoma need to be identified. In this study, we focused on deubiquitinating enzymes, which regulate protein stability through ubiquitin–proteasome systems, and identified 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) as a molecule related to melanoma growth using siRNA library screening. Similar to a previous report, PSMD14 knockdown strongly induced p21 expression and inhibited RB phosphorylation in melanoma. After in silico analysis, TGF-β signaling was identified as a negatively correlated gene set with PSMD14 expression. Although TGF-β signaling is also related to the invasive phenotype of melanoma, PSMD14 knockdown suppressed melanoma migration and reduced SLUG expression, suggesting that targeting PSMD14 suppresses both growth and migration. Furthermore, SMAD3 expression increased in nucleus and SMAD3 degradation was delayed after PSMD14 knockdown. Thus, our present study suggests that targeting PSMD14 can inhibit melanoma growth and migration through either SMAD3 accumulation or SLUG reduction, respectively.

Oncogenic changes in the non-canonical ERK-RSK-EphA2 axis drive migratory behavior in non-small cell lung cancer cells. However, the role of SHP2, a tyrosine phosphatase that regulates the RAS-ERK pathway, in the activation of EphA2 remains unknown. We herein demonstrated that the allosteric SHP2 inhibitors, SHP099 and TNO155, suppressed both the TNF-α- and growth factor-induced non-canonical phosphorylation of EphA2 at Ser-897 via the ERK-RSK pathway. The significant impact of SHP2 inhibitors on non-canonical EphA2 activation in lung adenocarcinoma (LUAD) cells harboring the EGFR exon 19 deletion (PC-9, HCC827), EML4-ALK rearrangement (A925L), and KRAS mutation (A549) was also examined, and the results obtained showed a reduction in cell migration in vitro and early metastatic processes in vivo . In contrast, these inhibitors did not affect the signaling pathways leading to EphA2 induced by TPA in HeLa cells or by TNF-α in A549 cells, indicating the involvement of a complex signaling network in these processes. Collectively, the present results highlight the potential of allosteric SHP2 inhibitors as agents targeting the non-canonical activation of EphA2 in LUAD cells.

The combination of oncogenes and tumor suppressors is involved in cancer development; however, it is still unknown whether their combination plays a critical role in cancer metastasis. We herein investigated whether genetic combinations affected cell migration ability by establishing the immortalized melanocytes, melan-a cells, with an oncogene, either BRAF V600E or GNA11 Q209L , and the loss of mouse Pten. The loss of mouse Pten or human PTEN increased the cell migration ability of our established cells and human melanoma cell lines with oncogenic MAPK signaling and the BRAF V600E or NRAS Q61R background, but not with the GNA11 Q209L background or no oncogenes. Although increased migration was not related to PI3K-AKT activation, those migration is regulated by the induction of some components in the WAVE regulatory complex, resulting in a higher rate of the formation of lamellipodia. On the other hand, BRAF V600E induced EphA2 phosphorylation at serine 897 through RSK and was also required for cell migration and the formation of lamellipodia. Therefore, the oncogenic MAPK pathway and loss of Pten in melanoma were important for cell migration through the formation of lamellipodia, suggesting the significance of an appropriate combination of genetic alterations not only in cancer development, but also cancer metastasis.

Although epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (EGFR‐TKI), including gefitinib, provide a significant clinical benefit in non‐small‐cell lung cancer (NSCLC) patients, the acquisition of drug resistance has been known to limit the efficacy of EGFR‐TKI therapy. In this study, we demonstrated the involvement of EGF‐EGFR signaling in NSCLC cell migration and the requirement of RAC1 in EGFR‐mediated progression of NSCLC. We showed the significant role of RAC1 pathway in the cell migration or lamellipodia formation by using gene silencing of RAC1 or induction of constitutive active RAC1 in EGFR‐mutant NSCLC cells. Importantly, the RAC1 inhibition suppressed EGFR‐mutant NSCLC cell migration and growth in vitro, and growth in vivo even in the gefitinib‐resistant cells. In addition, these suppressions by RAC1 inhibition were mediated through MEK or PI3K independent mechanisms. Collectively, these results open up a new opportunity to control the cancer progression by targeting the RAC1 pathway to overcome the resistance to EGFR‐TKI in NSCLC patients. We demonstrated that EGF‐EGFR signaling is involved in NSCLC cell migration through RAC1. RAC1 inhibition could also suppress the tumor growth even in gefitinib‐resistant NSCLC. Our present study opens up the new therapeutic potential of targeting the RAC1 pathway to control disease progression of EGFR‐mutant NSCLC to overcome resistance to EGFR‐TKIs.

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), including cetuximab and panitumumab, have been used in clinic settings to treat cancer. They have also recently been applied to antibody–drug conjugates (ADCs); however, their clinical efficacy is limited by several issues, including lower internalization efficiency. The binding of cetuximab to the extracellular domain of EGFR suppresses ligand-induced events; therefore, we focus on ligand-independent non-canonical EGFR endocytosis for the delivery of ADCs into cells. Tumor necrosis factor-α (TNF-α) strongly induces the endocytosis of the cetuximab-EGFR complex within 15 min via the p38 phosphorylation of EGFR in a tyrosine kinase-independent manner. A secondary antibody conjugated with saporin, a ribosome-inactivating protein, also undergoes internalization with the complex and enhances its anti-proliferative activity. Anti-cancer agents, including cisplatin and temozolomide, also induce the p38-mediated internalization. The results of the present study demonstrate that synchronous non-canonical EGFR endocytosis may be a feasible strategy for promoting the therapeutic efficacy of EGFR-targeting ADCs in clinical settings.

Host lipid metabolism and viral responses are intimately connected. However, the process by which the acquired immune systems adapts lipid metabolism to meet demands, and whether or not the metabolic rewiring confers a selective advantage to host immunity, remains unclear. Here we show that viral infection attenuates the expression of genes related to lipid metabolism in murine CD4+ T cells, which in turn increases the expression of antiviral genes. Inhibition of the fatty acid synthesis pathway substantially increases the basal expression of antiviral genes via the spontaneous production of type I interferon (IFN). Using a combination of CRISPR/Cas9-mediated genome editing technology and a global lipidomics analysis, we found that the decrease in monounsaturated fatty acid caused by genetic deletion of Scd2 in mice was crucial for the induction of an antiviral response through activation of the cGAS-STING pathway. These findings demonstrate the important relationship between fatty acid biosynthesis and type I IFN responses that enhances the antiviral response.Kanno et al. demonstrate that decreased monounsaturated fatty acid in CD4 + T cells following Scd2 deletion boosts the induction of the antiviral response via activation of the cGAS-STING pathway in mice. This study highlights the important interaction between fatty acid metabolism and the acquired immune response.

Although the heterogeneities of epithelial and mesenchymal‐transitioned cancer cells are often observed within the tumor microenvironment, the biological significance of the interaction between epithelial cancer cells and mesenchymal‐transitioned cancer cells is not yet understood. In this study, we show that the mesenchymal‐transitioned cancer cells instigate the invasive ability and metastatic potential of the neighboring epithelial cancer cells in vitro and in vivo. We identify WNT3 and WNT5B as critical factors secreted from Transforming growth factor‐induced mesenchymal cancer cells for instigating the epithelial cancer cell invasion along with the induction of secondary EMT phenotype. These results shed light on the significance of cancer heterogeneity and the interaction between epithelial and mesenchymal‐transitioned cancer cells within the tumor microenvironment in promoting metastatic disease through the WNT‐dependent mechanism. Our results shed the light on the significance of cancer heterogeneities and the interaction between epithelial and mesenchymal‐transitioned cancer cells within tumor microenvironment in promoting metastatic disease through WNT‐dependent mechanism.

Type I interferons (type I-IFN) are critical for the host defense to viral infection, and at the same time, the dysregulation of type I-IFN responses leads to autoinflammation or autoimmunity. Recently, we reported that the decrease in monounsaturated fatty acid caused by the genetic deletion of Scd2 is essential for the activation of type I-IFN signaling in CD4 + Th1 cells. Although interferon regulatory factor (IRF) is a family of homologous proteins that control the transcription of type I-IFN and interferon stimulated genes (ISGs), the member of the IRF family that is responsible for the type I-IFN responses induced by targeting of SCD2 remains unclear. Here, we report that the deletion of Scd2 triggered IRF3 activation for type I-IFN production, resulting in the nuclear translocation of IRF9 to induce ISG transcriptome in Th1 cells. These data led us to hypothesize that IRF9 plays an essential role in the transcriptional regulation of ISGs in Scd2 -deleted (sg Scd2 ) Th1 cells. By employing ChIP-seq analyses, we found a substantial percentage of the IRF9 target genes were shared by sg Scd2 and IFNβ-treated Th1 cells. Importantly, our detailed analyses identify a unique feature of IRF9 binding in sg Scd2 Th1 cells that were not observed in IFNβ-treated Th1 cells. In addition, our combined analyses of transcriptome and IRF9 ChIP-seq revealed that the autoimmunity related genes, which increase in patient with SLE, were selectively increased in sg Scd2 Th1 cells. Thus, our findings provide novel mechanistic insights into the process of fatty acid metabolism that is essential for the type I-IFN response and the activation of the IRF family in CD4 + T cells.

Non-small cell lung cancer (NSCLC) is one of the leading causes of death in all lung cancer patients due to its metastatic spread. Even though cisplatin treatment after surgical resection of the primary tumor has been established as a standard chemotherapy for residual disease including metastatic spread, NSCLC often acquires a resistance against chemotherapy, and metastatic disease is often observed. Amongst many potential mechanisms, epithelial-to-mesenchymal transition (EMT) has been considered as an important process in acquiring both metastatic spread and chemo-resistance of NSCLC. In this study, we identified MCL-1 as a critical molecule for chemo-resistance in A549 cells associated with TGF-β-induced EMT. Importantly, downregulation of MCL-1 by siRNA or inhibition of MCL-1 with pan-BCL2 inhibitor to inhibit MCL-1 was able to overcome the EMT-associated chemo-resistance in A549 cells. Collectively, MCL-1 can be a new therapeutic target for overcoming EMT-associated chemo-resistance in NSCLC patients in the context of post-operative chemotherapies.

Malignant melanoma has exhibited a rising incidence in recent years worldwide. Although various molecular targeted drugs are being researched and developed for melanoma patients, their efficacy appears to be unsatisfactory. Over the past few years, several reports have demonstrated that Coptidis Rhizoma water extracts (CR) or its major active chemical component, berberine, has anticancer activities in various types of cancer, including melanoma. However, their underlying mechanisms have not been well understood. In the present study, we determined that CR suppressed melanoma cell viability, which was mainly mediated through apoptosis. In addition, the expression levels of anti-apoptotic proteins, BCL2A1, MCL1 and BCL-w, were strongly suppressed by CR treatment. Furthermore, multi-domain pro-apoptotic proteins BAX and BAK were activated by CR treatment and were also required for the CR-induced apoptosis. Collectively, CR or some formulations containing CR, may be effective safe treatment strategies for human melanoma.