Cadmium promotes breast cancer cell proliferation, migration and invasion by inhibiting ACSS2/ATG5-mediated autophagy

Yidan Liang; Huifeng Pi; Lingzhi Liao; Miduo Tan; Ping Deng; Yang Yue; Yu Xi; Li Tian; Jia Xie; Mengyan Chen; Yan Luo; Mingliang Chen; Liting Wang; Zhengping Yu; Zhou Zhou

doi:10.1016/j.envpol.2021.116504

Cadmium promotes breast cancer cell proliferation, migration and invasion by inhibiting ACSS2/ATG5-mediated autophagy

Environ Pollut. 2021 Jan 15:273:116504. doi: 10.1016/j.envpol.2021.116504. Online ahead of print.

Authors

Yidan Liang¹, Huifeng Pi², Lingzhi Liao³, Miduo Tan⁴, Ping Deng², Yang Yue², Yu Xi⁵, Li Tian², Jia Xie², Mengyan Chen², Yan Luo², Mingliang Chen⁶, Liting Wang⁷, Zhengping Yu⁸, Zhou Zhou⁹

Affiliations

¹ School of Medicine, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China.
² Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing, China.
³ Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine (Central Hospital of Zhuzhou City), Central South University, Zhuzhou, Hunan, China.
⁴ Surgery Department of Galactophore, Zhuzhou Hospital Affiliated to Xiangya School of Medicine (Central Hospital of Zhuzhou City), Central South University, Zhuzhou, Hunan, China.
⁵ Department of Environmental Medicine, School of Public Health, And Department of Emergency Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁶ Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology, Ministry of Education, Southwest Hospital, Third Military Medical University, Chongqing, China.
⁷ Biomedical Analysis Center, Third Military Medical University, Chongqing, China.
⁸ School of Medicine, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China; Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing, China.
⁹ School of Medicine, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China; Department of Environmental Medicine, School of Public Health, And Department of Emergency Medicine, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: lunazhou@zju.edu.cn.

PMID: 33486244
DOI: 10.1016/j.envpol.2021.116504

Abstract

Cadmium (Cd), which is considered a carcinogenic metal, promotes breast cancer (BC) progression, but the precise mechanism remains unclear. Herein, MCF-7 and T47-D cells were treated with 0.1, 1, and 10 μM cadmium chloride (CdCl₂) for 24, 48 and 72 h. In our study, Cd exposure significantly accelerated the proliferation, migration and invasion of MCF-7 and T47-D cells. Notably, Cd inhibited autophagic flux by suppressing ATG5-dependent autophagosome formation but had no significant effect on autophagosome-lysosome fusion and lysosomal function. The genetic enhancement of autophagy through ATG5 overexpression suppressed the Cd-mediated increases in proliferation, migration and invasion, which indicated a carcinogenic role of autophagy impairment in Cd-exposed BC cells. GSEA and GeneMANIA were utilized to demonstrate that the Cd-induced decrease in ACSS2 expression mechanistically inhibited ATG5-dependent autophagy in BC cells. Importantly, ACSS2 overexpression increased the level of H3K27 acetylation in the promoter region of ATG5, and this result maintained autophagic flux and abolished the Cd-induced increases in proliferation, migration and invasion. We also verified that the expression of ACSS2 in BC tissues was low and positively related to ATG5 expression. These findings indicated that the promoting effect of Cd on BC cell proliferation, migration and invasion through the impairment of ACSS2/ATG5-dependent autophagic flux suggests a new mechanism for BC cell proliferation and metastasis stimulated by Cd.

Keywords: ACSS2; ATG5; Autophagy; Breast cancer; Cd.