Malignant melanoma is a type of very dangerous skin cancer. Histone modifiers usually become dysregulated during the process of carcinoma development, thus there is potential for a histone modifier inhibitor as a useful drug for cancer therapy. There is a multitude of evidence regarding the role of G9a, a histone methyltransferase (HMTase), in tumorigenesis. In this study, we first showed that G9a was significantly upregulated in melanoma patients. Using the TCGA database, we found a significantly higher expression of G9a in primary melanoma samples (n = 461) compared to normal skin samples (n = 551). Next, we knocked down G9a in human M14 and A375 melanoma cell lines in vitro via small interfering RNA (siRNA). This resulted in a significant decrease in cell viability, migration and invasion, and an increase in cell apoptosis. UNC0642 is a small molecule inhibitor of G9a that demonstrates minimal cell toxicity and good in vivo pharmacokinetic characteristics. We investigated the role of UNC0642 in melanoma cells, and detected its anti-cancer effects in vitro and in vivo. Next, we treated cells with UNC0642, and observed a significant decrease in cell viability in M14 and A375 cell lines. Furthermore, treatment with UNC0642 resulted in increased apoptosis. In immunocompetent mice bearing A375 engrafts, treatment with UNC0642 inhibited tumor growth. Results of Western blot analysis revealed that administration of UNC0642 or silencing of G9a expression by siRNA reduced Notch1 expression significantly and decreased the level of Hes1 in A375. All in all, the data from our study demonstrates potential of G9a as a therapeutic target in the treatment of melanoma.

Ferroptosis is a form of regulatory cell death distinct from caspase-dependent apoptosis and visualization of its process based on fluorescence imaging technology is important for life entities.

Epithelial-to-mesenchymal transition (EMT) plays an important role in invasion and metastasis of hepatocellular carcinoma (HCC). Our previous study found that atypical protein kinase C-ι (aPKC-ι) promoted the EMT process in HCC. However, how the aPKC-ι signaling pathway is regulated in HCC has not been elucidated. In this study, vector transfection was utilized to study the invasion of HCC cells, and the mechanism between P300 and aPKC-ι signaling pathways in regulating the EMT process of HCC was further elucidated in vitro and in vivo. We found both P300 and aPKC-ι were highly expressed in HCC and they were correlated with tumor progression and poor survival in HCC patients. P300 knockdown inhibited EMT, invasion and other malignant events of HCC cells but promoted cell apoptosis and cycle arrest. However, the effects mediated by P300 knockdown were abolished by aPKC-ι overexpression. Further studies showed that P300 upregulates aPKC-ι expression through increasing the transcription of Elk1, a transcriptional activator of aPKC-ι, and stabilizing Elk1 protein and its phosphorylation. In conclusion, our work uncovered the molecular mechanism by which oncogenic aPKC-ι is upregulated in HCC and suggests that P300, like aPKC-ι, may be used as a prognostic biomarker and therapeutic target in patients with HCC.

Background: Excision Repair Cross-Complementation group 6-like (ERCC6L) has been shown to exhibit carcinogenic effect in several malignant tumors. However, the function and molecular mechanism of the ERCC6L in hepatocellular carcinoma (HCC) have not been investigated extensively. Methods: Immunohistochemistry analyses were used to detect ERCC6L expression in a HCC tissue microarray, and the Chi-square test was used to assess the correlation between ERCC6L expression and patients' clinicopathological features. shRNA was used to down-regulation ERCC6L expression in HCC cell lines. MTT assay, plate clone formation assay, flow cytometry, caspase 3/7 activity and migration assays were performed to evaluate the impact of ERCC6L on HCC cells in vitro. Nude mice xenograft models were used to assess the role of ERCC6L in vivo. The regulatory of mechanism of PI3K/AKT pathway was evaluated by western blotting. Results: ERCC6L was highly expressed in HCC tissue compared with tumor adjacent tissues in 90 paired samples. ERCC6L expression positively correlated with gender, tumor encapsulation, and pathological stage. Patients with low ERCC6L expression had significantly longer OS than those with high ERCC6L expression. Knockdown of ERCC6L expression significantly inhibited proliferation, invasion and metastasis in vitro and tumor growth in vivo, and it promoted cell cycle arrest and apoptosis. Mechanistic analyses revealed that PI3K/AKT and NF-κB signaling pathway were inhibited by silencing ERCC6L. Conclusion: These results demonstrate that ERCC6L plays a critical role in HCC progression, and thereby might be a potential therapeutic target for HCC patients.