Multi-omics approaches identify SF3B3 and SIRT3 as candidate autophagic regulators and druggable targets in invasive breast carcinoma

Shouyue Zhang; Jin Zhang; Yang An; Xiaoxi Zeng; Ziyi Qin; Yuqian Zhao; Heng Xu; Bo Liu

doi:10.1016/j.apsb.2020.12.013

Multi-omics approaches identify SF3B3 and SIRT3 as candidate autophagic regulators and druggable targets in invasive breast carcinoma

Acta Pharm Sin B. 2021 May;11(5):1227-1245. doi: 10.1016/j.apsb.2020.12.013. Epub 2020 Dec 19.

Authors

Shouyue Zhang^{1

2}, Jin Zhang^{1

2

3}, Yang An^{4

5}, Xiaoxi Zeng⁶, Ziyi Qin^{1

2}, Yuqian Zhao^{1

2}, Heng Xu², Bo Liu¹

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 61004, China.
² Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
³ School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China.
⁴ Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China.
⁵ Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu 610041, China.

Abstract

Autophagy is a critical cellular homeostatic mechanism, and its dysfunction is linked to invasive breast carcinoma (BRCA). Recently, several omics methods have been applied to explore autophagic regulators in BRCA; however, more reliable and robust approaches for identifying crucial regulators and druggable targets remain to be discovered. Thus, we report here the results of multi-omics approaches to identify potential autophagic regulators in BRCA, including gene expression (EXP), DNA methylation (MET) and copy number alterations (CNAs) from The Cancer Genome Atlas (TCGA). Newly identified candidate genes, such as SF3B3, TRAPPC10, SIRT3, MTERFD1, and FBXO5, were confirmed to be involved in the positive or negative regulation of autophagy in BRCA. SF3B3 was identified firstly as a negative autophagic regulator, and siRNA/shRNA-SF3B3 were shown to induce autophagy-associated cell death in in vitro and in vivo breast cancer models. Moreover, a novel small-molecule activator of SIRT3, 1-methylbenzylamino amiodarone, was discovered to induce autophagy in vitro and in vivo. Together, these results provide multi-omics approaches to identify some key candidate autophagic regulators, such as the negative regulator SF3B3 and positive regulator SIRT3 in BRCA, and highlight SF3B3 and SIRT3 as new druggable targets that could be used to fill the gap between autophagy and cancer drug development.

Keywords: ATG, autophagy-related gene; Anti-proliferation; Autophagic regulator; BRCA, invasive breast carcinoma; CNA, copy number alteration; Druggable target; EXP, gene expression; GO, Gene Ontology; Invasive breast carcinoma; LASSO, least absolute shrinkage and selection operator; MET, DNA methylation; Migration; Multi-omics approach; PFS, progression-free survival; SF3B3; SIRT3; SNF, similarity network fusion; TCGA, The Cancer Genome Atlas; TNBC, triple-negative breast cancer.