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

Oncogene volume 41, pages 2390–2403 (2022)Cite this article

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A Correction to this article was published on 14 June 2022

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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.

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Fig. 1: SIK2 expression is positively correlated with breast cancer recurrence.
Fig. 2: SIK2 is critical for the stemness of BCSCs.
Fig. 3: Interference with SIK2 inhibits the tumor initiation of breast cancer cells in vivo.
Fig. 4: SIK2 activates the Wnt/β-catenin signaling pathway, participating in the development of zebrafish embryos.
Fig. 5: SIK2 binds to CK1α to activate the Wnt/β-catenin pathway, and this process depends on the kinase activity of SIK2.
Fig. 6: T169 of CK1α is critical for the phosphorylation of SIK2.
Fig. 7: SIK2 directly phosphorylates the Wnt receptor LRP6 to activate the Wnt/β-catenin pathway.
Fig. 8: SIK2 promotes IDH1 expression through the Wnt/β-catenin pathway in breast cancer cells.

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Data availability

RNA-Seq data released: Gene Expression Omnibus GSE169344.

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Acknowledgements

This work was supported partly by National Natural Science Foundation of China (81874200, 82030087, 82103675, 82172980, and 82060308), Fund 2018RS3028, and 2021JJ0039 from Hunan Provincial Science and Technology Department and Guizhou Science and Technology Immunology and infection Platform (2018-5706 and 2017-5724).

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Authors and Affiliations

  1. Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China

    Zhuoxian Rong, Lu Zhang, Zhi Li, 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, Rong Tan, Liang Weng, Yuezhen Deng & Lunquan Sun

  2. Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China

    Zhuoxian Rong, Lu Zhang, Zhi Li, 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, Rong Tan, Liang Weng, Yuezhen Deng & Lunquan Sun

  3. Institute of Gerontological Cancer Research, National Clinical Research Center for Gerontology, Changsha, 410008, China

    Zhuoxian Rong, Zhi Li, Jiang He, Rong Tan, Liang Weng, Yuezhen Deng & Lunquan Sun

  4. Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, 410008, China

    Zhuoxian Rong, Zhi Li, Rong Tan, Liang Weng, Yuezhen Deng & Lunquan Sun

  5. Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, 410008, China

    Zhuoxian Rong, Zhi Li, Rong Tan, Liang Weng, Yuezhen Deng & Lunquan Sun

  6. Deparment of Breast Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China

    Zhi Xiao

  7. Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China

    Yumei Duan

  8. NHC Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People’s Hospital, Guiyang, 550000, China

    Yingjie Nie

  9. College of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China

    Yuhao Li & Rong Xiang

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Contributions

LS, YD, and ZR designed the experiments and wrote the paper. ZR, LZ, ZL, YL, and RX performed the xenograft tumor and Zebrafish experiments. ZR, ZX, YD, and YZ processed clinical specimens. DO, JH, ZR, and XR performed the kinase screening. ZR, JG, and YM performed the ChIP experiments. ZR, YZ, and YG performed IHC and pathological analysis. ZR, ZZ, ZC, and QF.

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Correspondence to Yuezhen Deng or Lunquan Sun.

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Rong, Z., Zhang, L., Li, Z. et al. SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling. Oncogene 41, 2390–2403 (2022). https://doi.org/10.1038/s41388-022-02259-0

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