SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling

Zhuoxian Rong; Lu Zhang; Zhi Li; Zhi Xiao; Yumei Duan; Xinxin Ren; Yuyuan Zi; Jie Gao; Yun Mu; Yidi Guan; Zhen Cao; Xitao Wang; Qian Pei; Yu Zeng; Qi Fan; Zimei Zeng; Danmin Ou; Jiang He; Yingjie Nie; Rong Tan; Liang Weng; Yuhao Li; Rong Xiang; Yuezhen Deng; Lunquan Sun

doi:10.1038/s41388-022-02259-0

SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling

Oncogene. 2022 Apr;41(16):2390-2403. doi: 10.1038/s41388-022-02259-0. Epub 2022 Mar 11.

Authors

Zhuoxian Rong^{1

2

3

4

5}, Lu Zhang^{1

2}, Zhi Li^{1

2

3

4

5}, Zhi Xiao⁶, Yumei Duan⁷, Xinxin Ren^{1

2}, Yuyuan Zi^{1

2}, Jie Gao^{1

2}, Yun Mu^{1

2}, Yidi Guan^{1

2}, Zhen Cao^{1

2}, Xitao Wang^{1

2}, Qian Pei^{1

2}, Yu Zeng^{1

2}, Qi Fan^{1

2}, Zimei Zeng^{1

2}, Danmin Ou^{1

2}, Jiang He^{1

2

3}, Yingjie Nie⁸, Rong Tan^{1

2

3

4

5}, Liang Weng^{1

2

3

4

5}, Yuhao Li⁹, Rong Xiang⁹, Yuezhen Deng^{10

11

12

13

14}, Lunquan Sun^{15

16

17

18

19}

Affiliations

¹ Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
² Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China.
³ Institute of Gerontological Cancer Research, National Clinical Research Center for Gerontology, Changsha, 410008, China.
⁴ Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, 410008, China.
⁵ Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, 410008, China.
⁶ Deparment of Breast Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
⁷ Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China.
⁸ NHC Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People's Hospital, Guiyang, 550000, China.
⁹ College of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
¹⁰ Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China. yuezhendeng@csu.edu.cn.
¹¹ Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China. yuezhendeng@csu.edu.cn.
¹² Institute of Gerontological Cancer Research, National Clinical Research Center for Gerontology, Changsha, 410008, China. yuezhendeng@csu.edu.cn.
¹³ Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, 410008, China. yuezhendeng@csu.edu.cn.
¹⁴ Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, 410008, China. yuezhendeng@csu.edu.cn.
¹⁵ Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China. lunquansun@csu.edu.cn.
¹⁶ Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China. lunquansun@csu.edu.cn.
¹⁷ Institute of Gerontological Cancer Research, National Clinical Research Center for Gerontology, Changsha, 410008, China. lunquansun@csu.edu.cn.
¹⁸ Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, 410008, China. lunquansun@csu.edu.cn.
¹⁹ Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, 410008, China. lunquansun@csu.edu.cn.

PMID: 35277657
DOI: 10.1038/s41388-022-02259-0

Abstract

Breast cancer stem cells (BCSCs) are the main drivers of recurrence and metastasis. However, commonly used drugs rarely target BCSCs. Via screenings, we found that Salt-inducible kinase 2 (SIK2) participated in breast cancer (BC) stemness maintenance and zebrafish embryos development. SIK2 was upregulated in recurrence samples. Knockdown of SIK2 expression reduced the proportion of BCSCs and the tumor initiation of BC cells. Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation. ARN-3236 and HG-9-91-01, inhibitors of SIK2, inhibited LRP6 phosphorylation and β-catenin accumulation and disturbed stemness maintenance. In addition, the SIK2-activated Wnt/β-catenin signaling led to induction of IDH1 expression, causing metabolic reprogramming in BC cells. These findings demonstrate a novel mechanism whereby Wnt/β-catenin signaling pathway is regulated by different kinases in response to metabolic requirement of CSCs, and suggest that SIK2 inhibition may potentially be a strategy for eliminating BCSCs.

MeSH terms

Animals
Breast Neoplasms* / pathology
Cell Line, Tumor
Female
Humans
Low Density Lipoprotein Receptor-Related Protein-6* / genetics
Low Density Lipoprotein Receptor-Related Protein-6* / metabolism
Protein Serine-Threonine Kinases* / genetics
Wnt Signaling Pathway*
Zebrafish / metabolism
beta Catenin / genetics
beta Catenin / metabolism

Substances

LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-6
beta Catenin
salt-inducible kinase-2, human
Protein Serine-Threonine Kinases