Abstract 374: KMT2A promotes tumor growth by activating hTERT and CBP signaling and predicts poor prognosis in human melanoma

Abstract

Abstract Melanoma is an aggressive type of cutaneous malignancy. Although the inhibitors targeting BRAF and/or MEK pathways provide a therapeutic option for non-resectable melanoma driven by BRAF mutation, melanoma, especially metastatic melanoma, has still become one of the most threatening malignancies. Thus, identifying the exact molecular mechanisms involved in melanoma growth and discovering the novel targets for melanoma therapy is urgently needed. In this study, we screened a siRNA library targeting 6024 human genes in human melanoma cells and identified KMT2A as a potential therapeutic target for melanoma. KMT2A was highly expressed in melanoma cell lines and tumor tissues of melanoma patients. Knockdown of KMT2A by siRNA or shRNA significantly inhibited cell viability and colony formation, whereas exogenous expression of KMT2A effectively promoted cell growth in various melanoma cell lines. Further mechanism studies showed that the KMT2A-mediated regulation of melanoma growth was through targeting the hTERT and CBP signaling. Knockdown of KMT2A significantly inhibited hTERT promoter activity and protein expression and attenuated telomerase activity. Overexpression of hTERT rescued the KMT2A knockdown-mediated melanoma cell growth. By contrast, exogenous expression of KMT2A activated hTERT transcription and expression and increased telomerase activity in melanoma cells. Moreover, we found that KMT2A promoted hTERT expression and melanoma cell growth by cooperating with the transcriptional co-activator CBP, which interacted with and acetylated KMT2A. Inhibition of CBP by siRNA or a CBP-specific inhibitor suppressed the acetylation of KMT2A, abrogated the binding of KMT2A on the hTERT promoter and down-regulated hTERT expression, thereby inhibiting the growth of melanoma cells. Conversely, overexpression of CBP increased KMT2A acetylation and the binding to hTERT promoter, resulting in the promotion of hTERT expression and cell growth. The in vivo studies also showed that KMT2A promoted melanoma growth by activating the hTERT signaling in a xenograft tumor mouse model. Furthermore, the analyses for the clinical samples demonstrated that KMT2A expression was positively correlated with hTERT in tumor tissues of melanoma patients, and the high expression of both KMT2A and hTERT was associated with the worse clinical TNM staging and poor prognosis in melanoma patients. Taken together, our results indicate that KMT2A promotes melanoma growth by activating hTERT and CBP signaling in human melanoma. Our study therefore provides new insights into understanding the regulatory mechanism of melanoma growth and suggests that the KMT2A/CBP/hTERT signaling may be a potential therapeutic target for human melanoma. Funding support: This work was supported by the funds from the National Natural Science Foundation of China (81071687, 81272195), the State “973 Program” of China (2014CB542005). Citation Format: Changlin Zhang, Ranran Tang, Kefang Zhang, Wenlin Huang, Wuguo Deng. KMT2A promotes tumor growth by activating hTERT and CBP signaling and predicts poor prognosis in human melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 374. doi:10.1158/1538-7445.AM2017-374