Abstract
Melanoma is an aggressive cutaneous malignancy, illuminating the exact mechanisms and finding novel therapeutic targets are urgently needed. In this study, we identified KMT2A as a potential target, which promoted the growth of human melanoma cells. KMT2A knockdown significantly inhibited cell viability and cell migration and induced apoptosis, whereas KMT2A overexpression effectively promoted cell proliferation in various melanoma cell lines. Further study showed that KMT2A regulated melanoma cell growth by targeting the hTERT-dependent signal pathway. Knockdown of KMT2A markedly inhibited the promoter activity and expression of hTERT, and hTERT overexpression rescued the viability inhibition caused by KMT2A knockdown. Moreover, KMT2A knockdown suppressed tumorsphere formation and the expression of cancer stem cell markers, which was also reversed by hTERT overexpression. In addition, the results from a xenograft mouse model confirmed that KMT2A promoted melanoma growth via hTERT signaling. Finally, analyses of clinical samples demonstrated that the expression of KMT2A and hTERT were positively correlated in melanoma tumor tissues, and KMT2A high expression predicted poor prognosis in melanoma patients. Collectively, our results indicate that KMT2A promotes melanoma growth by activating the hTERT signaling, suggesting that the KMT2A/hTERT signaling pathway may be a potential therapeutic target for melanoma.
Highlights
There may be one million melanoma patients in the United States
The results showed that knockdown of KMT2A by its specific shRNAs inhibited the expression of KMT2A (Figure 1b and Supplementary Fig. 1A), whereas overexpression of KMT2A markedly increased the expression of KMT2A (Figure 1c and Supplementary Fig. 1B)
KMT2A was identified as a candidate target from a siRNA library screening, and we found that KMT2A knockdown inhibited cell proliferation, promoted apoptosis and suppressed the growth of melanoma xenograft
Summary
There may be one million melanoma patients in the United States. Up to 20% of the patients will develop metastatic tumors eventually, and the 5-year survival rate of them is o5% after the occurrence of metastasis.[5]. Lysine methyltransferase 2A (KMT2A), known as mixed-lineage leukemia (MLL) or acute lymphoblastic leukemia 1 (ALL-1), is a transcriptional co-activator regulating gene expression during early development and hematopoiesis.[13,14] The KMT2A protein contains multiple conserved functional domains,[15] and the SET domain is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity that mediates chromatin modifications associated with epigenetic transcriptional activation.[16,17] KMT2A is processed by taspase 1 into two fragments, MLL-C and MLL-N. Our study has revealed the role of KMT2A in melanoma progression for the first time, and identified a potential therapeutic target for melanoma treatment
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