Protocatechuic Aldehyde Represses Proliferation and Migration of Breast Cancer Cells through Targeting C-terminal Binding Protein 1

Yu Deng; Wanjun Guo; Guancheng Li; Shuang Li; Hong Li; Xinyan Li; Bei Niu; Mingzhu Song; Yamei Zhang; Zhijian Xu; Fulun Li

doi:10.4048/jbc.2020.23.e7

Protocatechuic Aldehyde Represses Proliferation and Migration of Breast Cancer Cells through Targeting C-terminal Binding Protein 1

J Breast Cancer. 2020 Feb;23(1):20-35. doi: 10.4048/jbc.2020.23.e7.

Authors

Yu Deng^{1

2}, Wanjun Guo³, Guancheng Li⁴, Shuang Li⁵, Hong Li⁶, Xinyan Li⁷, Bei Niu¹, Mingzhu Song¹, Yamei Zhang⁸, Zhijian Xu⁹, Fulun Li³

Affiliations

¹ School of Medicine, Chengdu University, Chengdu, China.
² Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, China.
³ Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁴ The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁵ Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China.
⁶ Department of Dermatology, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
⁷ Department of Epidemiology and Biostatistics, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO, USA.
⁸ Central Lab, Chengdu Univerisity Hospital, Chengdu, China.
⁹ CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Abstract

Purpose: C-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor that is overexpressed in many cancers. CtBP1 transcriptionally represses a broad array of tumor suppressors, which promotes cancer cell proliferation, migration, invasion, and resistance to apoptosis. Recent studies have demonstrated that CtBP1 is a potential target for cancer therapy. This study was designed to screen for compounds that potentially target CtBP1.

Methods: Using a structure-based virtual screening for CtBP1 inhibitors, we found protocatechuic aldehyde (PA), a natural compound found in the root of a traditional Chinese herb, Salvia miltiorrhiza, that directly binds to CtBP1. Microscale thermophoresis assay was performed to determine whether PA and CtBP1 directly bind to each other. Further, clustered regularly interspaced short palindromic repeats associated Cas9 nuclease-mediated CtBP1 knockout in breast cancer cells was used to validate the CtBP1 targeting specificity of PA.

Results: Functional studies showed that PA repressed the proliferation and migration of breast cancer cells. Furthermore, PA elevated the expression of the downstream targets of CtBP1, p21 and E-cadherin, and decreased CtBP1 binding affinity for the promoter regions of p21 and E-cadherin in breast cancer cells. However, PA did not affect the expression of p21 and E-cadherin in the CtBP1 knockout breast cancer cells. In addition, the CtBP1 knockout breast cancer cells showed resistance to PA-induced repression of proliferation and migration.

Conclusion: Our findings demonstrated that PA directly bound to CtBP1 and inhibited the growth and migration of breast cancer cells through CtBP1 inhibition. Structural modifications of PA are further required to enhance its binding affinity and selectivity for CtBP1.

Keywords: Breast neoplasms; C-terminal binding protein; Protocatechualdehyde.