Veratramine modulates AP-1-dependent gene transcription by directly binding to programmable DNA

Fang Bai, Kangdong Liu, Huiliang Li, Jiawei Wang, Junsheng Zhu, Pei Hao, Lili Zhu, Shoude Zhang, Lei Shan, Wei-Ya Ma, Ann M. Bode, Weidong Zhang, Honglin Li, Zigang Dong

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Because the transcription factor activator protein-1 (AP-1) regulates a variety of protein-encoding genes, it is a participant in many cellular functions, including proliferation, transformation, epithelial mesenchymal transition (EMT), and apoptosis. Inhibitors targeting AP-1 have potential use in the treatment of cancer and other inflammatory diseases. Here, we identify veratramine as a potent natural modulator of AP-1, which selectively binds to a specific site (TRE 5'-TGACTCA-3') of the AP-1 target DNA sequence and regulates AP-1-dependent gene transcription without interfering with cystosolic signaling cascades that might lead to AP-1 activation. Moreover, RNA-seq experiments demonstrate that veratramine does not act on the Hedgehog signaling pathway in contrast to its analogue, cyclopamine, and likely does not harbor the same teratogenicity and toxicity. Additionally, veratramine effectively suppresses EGF-induced AP-1 transactivation and transformation of JB6 P+ cells. Finally, we demonstrate that veratramine inhibits solar-ultraviolet-induced AP-1 activation in mice. The identification of veratramine and new findings in its specific regulation of AP-1 down stream genes pave ways to discovering and designing regulators to regulate transcription factor.

Original languageEnglish (US)
Pages (from-to)546-557
Number of pages12
JournalNucleic acids research
Volume46
Issue number2
DOIs
StatePublished - Jan 25 2018

Bibliographical note

Funding Information:
National Key Research and Development Program [2016YFA0502304 to H.L.L.]; Professor of Chang Jiang Scholars Program (to W.D.Z); National Natural Science Foundation of China [81372269 to K.D.L., 81230090, 81520108030, 21472238 to W.D.Z.]; Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products [16DZ2280200 to W.D.Z.]; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) [U1501501]; Honglin Li is also sponsored National Program for Support of Top-notch Young Professionals. Funding for open access charge: National Key Research and Development Program [2016YFA0502304]. Conflict of interest statement. None declared.

Publisher Copyright:
© The Author(s) 2017.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Fingerprint Dive into the research topics of 'Veratramine modulates AP-1-dependent gene transcription by directly binding to programmable DNA'. Together they form a unique fingerprint.

Cite this