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Title: The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells

Abstract

Melanoma is the most common primary malignant neoplasm in adults, causing more deaths than any other skin cancer, necessitating the development of new target-based approaches. Current evidence suggests SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD{sup +} biosynthetic enzyme, together comprise a novel systemic regulatory network to play a pivotal role in cell proliferation and apoptosis. Nevertheless, how the regulation of this cofactor interfaces with signal transduction network remains poorly understood in melanoma. Here, we report NAMPT is highly expressed in melanomaassociated with poor overall survival in patients. Pharmacological and genetic inhibition of NAMPT decreased NAD{sup +} levels and melanoma cell proliferation capacity, and NAMPT knockdown induced apoptosis through the activity of the tumor suppressor p53. Next, we demonstrate NAMPT regulates the transcription factor E2F family member 2 (E2F2) in the apoptosis process. Downstream, E2F2 control the mRNA and protein levels of SIRT1. Finally, we find NAMPT mediates the apoptosis resistance of melanoma cells through NAMPT-E2F2-SIRT1 axis, more than NAD{sup +}-driven transcriptional program. Accordingly, our results demonstrated that NAMPT is a prognostic marker in melanoma, and the identificationofNAMPT-E2F2-SIRT1 pathway establishes another link between NAMPT and apoptosis events in melanoma, with therapeuticmore » implications for this deadly cancer. - Highlights: • The expression of NAMPT is remarkably high in melanoma tumors and associated with poor overall survival in patients. • NAMPT is required for E2F2 and SIRT1 expression for regulating p53 and apoptosis levels in human melanoma cells. • NAMPT/E2F2/SIRT1 is a novel regulatory pathway that governs melanoma cells proliferation and apoptosis resistance.« less

Authors:
; ; ; ; ; ;
Publication Date:
OSTI Identifier:
22719117
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 493; Journal Issue: 1; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADENINES; APOPTOSIS; CELL PROLIFERATION; DEATH; ENZYMES; GENETICS; INHIBITION; MELANOMAS; MESSENGER-RNA; NAD; NICOTINAMIDE; PATIENTS; SKIN; TRANSCRIPTION; TRANSCRIPTION FACTORS

Citation Formats

Zhao, Hailong, Tang, Weiwei, Chen, Xiaowen, Wang, Siyu, Wang, Xianyan, Xu, Haiyan, and Li, Lijuan. The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2017.09.071.
Zhao, Hailong, Tang, Weiwei, Chen, Xiaowen, Wang, Siyu, Wang, Xianyan, Xu, Haiyan, & Li, Lijuan. The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells. United States. doi:10.1016/J.BBRC.2017.09.071.
Zhao, Hailong, Tang, Weiwei, Chen, Xiaowen, Wang, Siyu, Wang, Xianyan, Xu, Haiyan, and Li, Lijuan. Sat . "The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells". United States. doi:10.1016/J.BBRC.2017.09.071.
@article{osti_22719117,
title = {The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells},
author = {Zhao, Hailong and Tang, Weiwei and Chen, Xiaowen and Wang, Siyu and Wang, Xianyan and Xu, Haiyan and Li, Lijuan},
abstractNote = {Melanoma is the most common primary malignant neoplasm in adults, causing more deaths than any other skin cancer, necessitating the development of new target-based approaches. Current evidence suggests SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD{sup +} biosynthetic enzyme, together comprise a novel systemic regulatory network to play a pivotal role in cell proliferation and apoptosis. Nevertheless, how the regulation of this cofactor interfaces with signal transduction network remains poorly understood in melanoma. Here, we report NAMPT is highly expressed in melanomaassociated with poor overall survival in patients. Pharmacological and genetic inhibition of NAMPT decreased NAD{sup +} levels and melanoma cell proliferation capacity, and NAMPT knockdown induced apoptosis through the activity of the tumor suppressor p53. Next, we demonstrate NAMPT regulates the transcription factor E2F family member 2 (E2F2) in the apoptosis process. Downstream, E2F2 control the mRNA and protein levels of SIRT1. Finally, we find NAMPT mediates the apoptosis resistance of melanoma cells through NAMPT-E2F2-SIRT1 axis, more than NAD{sup +}-driven transcriptional program. Accordingly, our results demonstrated that NAMPT is a prognostic marker in melanoma, and the identificationofNAMPT-E2F2-SIRT1 pathway establishes another link between NAMPT and apoptosis events in melanoma, with therapeutic implications for this deadly cancer. - Highlights: • The expression of NAMPT is remarkably high in melanoma tumors and associated with poor overall survival in patients. • NAMPT is required for E2F2 and SIRT1 expression for regulating p53 and apoptosis levels in human melanoma cells. • NAMPT/E2F2/SIRT1 is a novel regulatory pathway that governs melanoma cells proliferation and apoptosis resistance.},
doi = {10.1016/J.BBRC.2017.09.071},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 493,
place = {United States},
year = {2017},
month = {11}
}