SETDB2 promoted breast cancer stem cell maintenance by interaction with and stabilization of ΔNp63α protein

Liu Ying^1*, Xie Fei^6*, Li Jialun^4,7, Xiao Jianpeng^2,3, Wang Jie^2,3, Mei Zhaolin¹, Fan Hongjia^2,3, Fang Huan¹, Li Sha¹, Wu Qiuju⁴, Yuan Lin⁴, Liu Cuicui⁴, Peng You⁴, Zhao Weiwei⁴, Wang Lulu⁴, Wong Jiemin⁷, Li Jing^2,4,5✉, Feng Jing^2,4,5✉

1. Anhui University of Science and Technology Affiliated Fengxian Hospital, Shanghai 201499, China
2. Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai 201499, China
3. The Third School of Clinical Medicine, Southern Medical University, Guangdong Province, Guangzhou 510515, China
4. Shanghai University of Medicine & Health Sciences, Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
5. Joint Research Center for Precision Medicine, Shanghai Jiao Tong University & Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
6. Department of clinical laboratory, Taihe Hospital, Hubei University of Medicine, 29 South Renmin Road, Shiyan, Hubei 442000, China
7. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
*: Liu Ying and Xie Fei contributed equally to this work.

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Citation:
Ying L, Fei X, Jialun L, Jianpeng X, Jie W, Zhaolin M, Hongjia F, Huan F, Sha L, Qiuju W, Lin Y, Cuicui L, You P, Weiwei Z, Lulu W, Jiemin W, Jing L, Jing F. SETDB2 promoted breast cancer stem cell maintenance by interaction with and stabilization of ΔNp63α protein. Int J Biol Sci 2020; 16(12):2180-2191. doi:10.7150/ijbs.43611. Available from http://www.ijbs.com/v16p2180.htm

Abstract

The histone H3K9 methyltransferase SETDB2 is involved in cell cycle dysregulation in acute leukemia and has oncogenic roles in gastric cancer. In our study, we found that SETDB2 plays essential roles in breast cancer stem cell maintenance. Depleted SETDB2 significantly decreased the breast cancer stem cell population and mammosphere formation in vitro and also inhibited breast tumor initiation and growth in vivo. Restoring SETDB2 expression rescued the defect in breast cancer stem cell maintenance. A mechanistic analysis showed that SETDB2 upregulated the transcription of the ΔNp63α downstream Hedgehog pathway gene. SETDB2 also interacted with and methylated ΔNp63α, and stabilized ΔNp63α protein. Restoring ΔNp63α expression rescued the breast cancer stem cell maintenance defect which mediated by SETDB2 knockdown. In conclusion, our study reveals a novel function of SETDB2 in cancer stem cell maintenance in breast cancer.

Keywords: Breast cancer stem cell, SETDB2, Hedgehog pathway, ΔNp63α, stability