KRas-ERK signalling promotes the onset and maintenance of uveal melanoma through regulating JMJD6-mediated H2A.X phosphorylation at tyrosine 39

Abstract

Since DNA damage is a first incident occurred during a tumour attack, it is rational that histone H2A.X phosphorylation on tyrosine 39 (H2A.X Y39ph) may act as a tumour-relevant factor. This study was aimed to test the authenticity of the hypothesis. Uveal melanoma MP65 cells were transfected for expression of KRas mutated. H2A.X phosphorylation and ERK1/2 was measured, and transwell experiment was performed to examine the consequents of H2A.X Y39ph on MP65 cells developing and migration. Regulatory relationship between H2A.X Y39ph and ERK1/2 downstream genes were measured. Moreover, whether JMJD6 and MDM2 are involved in H2A.X phosphorylation was studied. Mutation of Ras activated ERK1/ 2 signalling and inhibited H2A.X phosphorylation at Y39. Silence of H2A.X Y39ph contributed to the regulation of MP65 cells growth, migration and transcription of ERK1/2 downstream genes, including CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16. The repressed H2A.X phosphorylation through Ras-ERK1/2 signalling might be through MDM2-mediated JMJD6 degradation. Our study suggested that Ras-ERK1/2 signalling inhibited H2A.X phosphorylation at Y39, which led to the uncontrolled developing and migration of uveal melanoma cells. In addition, H2A.X phosphorylation was mediated possibly through JMJD6 which could be degraded by MDM2.

Screening and identification of key genes and pathways in metastatic uveal melanoma based on gene expression using bioinformatic analysis

“…[ 34 ] Blood coagulation pathways play a role in tumor progression and metastasis, [ 35 – 37 ] phosphor-AKT protein levels are positively associated with a higher risk for metastasis in patients with UM, [ 26 ] and ERK pathway promotes carcinogenesis and maintenance of UM. [ 38 ] Thus, results of all of these studies support those of the current investigation.…”

JMJD2C mediates the MDM2/p53/IL5RA axis to promote CDDP resistance in uveal melanoma

“…Notably, mounting evidence has demonstrated the oncogenic role of MDM2 in melanoma. For instance, MDM2 could regulate JMJD6 degradation to diminish H2A.X phosphorylation, thereby resulting in uncontrolled uveal melanoma cell migration [ 19 ]. Stabilized MDMX-MDM2 complex by AXL receptor signal inhibited p53 in melanoma, which could reduce the sensitivity of tumor cells to CDDP [ 20 ].…”

A Novel Four Genes of Prognostic Signature for Uveal Melanoma

“…Besides, Kirsten rat sarcoma viral oncogene homolog (KRAS) regard as the most lethal cancer-related proteins takes a crucial role in human aggressive cancers [ 23 ]. Previous study demonstrated that the activation of KRAS-ERK signaling can promote development and migration of uveal melanoma cells [ 49 ]. Meanwhile, we observed that interferon gamma, interferon alpha, and inflammatory response were actively enriched in the low-risk subgroup.…”