KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

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.

LncRNA OIP5-AS1 is overexpressed in undifferentiated oral tumors and integrated analysis identifies as a downstream effector of stemness-associated transcription factors

“…KMT2A is preferentially expressed in glioma stem cells and downregulation reduces CSC self-renewal and tumorigenicity 36 . KMT2A has been found to interact with the NF-κB pathway to regulate brain cancer growth and promotes melanoma growth by activating the hTERT signaling 37 . Knockdown of KMT2A suppressed tumorsphere formation and the expression of cancer stem cell markers 37 .…”

“…KMT2A has been found to interact with the NF-κB pathway to regulate brain cancer growth and promotes melanoma growth by activating the hTERT signaling 37 . Knockdown of KMT2A suppressed tumorsphere formation and the expression of cancer stem cell markers 37 . Similarly, KMT2C is also shown to play roles in metastasis of esophageal squamous cell carcinoma and knockdown experiments showed EMT-like morphological change in pancreatic cancer cell lines 38 .…”

<p>MicroRNA-769-5p Promotes The Growth Of Glioma Cells By Targeting Lysine Methyltransferase 2A</p>

“…The biological role of KMT2A has been widely investigated in human cancers 27–32. In melanoma, KMT2A contributes to tumor growth via inducing the activation of hTERT signaling28 KMT2A fusions and rearrangements are frequently detected in hematological malignancies 29–31. Moreover, KMT2A is highly expressed in CRC tissues and promotes cancer cell migration and invasion via epigenetically regulating cathepsin Z (CTSZ)32 Notably, KMT2A knockdown facilitates glioma cell proliferation and promotes tumor growth in vivo by epigenetically regulating notch receptor 1 (NOTCH1) and NOTCH3, suggesting a tumor suppressive role of KMT2A in glioma 27.…”

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

“…For instance, the hub Kmt2a (lysine methyltransferase 2A) from the blue module (Fig. 1 c, Table 1 ) is responsible for H3K4 methylation and associated with melanoma growth [ 49 ]. Other gene modules directly or inversely correlated with metastasis were enriched with the histone marks H3K4me3 (magenta and yellow), H3K36me3 (magenta, blue, yellow) and H3K79me2 (black, green yellow, light cyan), and H3K27ac (blue, black, magenta).…”