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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RNA-Seq data released: Gene Expression Omnibus GSE169344.
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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).
The authors declare no competing interests.
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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