| Literature DB >> 35277657 |
Zhuoxian Rong1,2,3,4,5, Lu Zhang1,2, Zhi Li1,2,3,4,5, Zhi Xiao6, Yumei Duan7, Xinxin Ren1,2, Yuyuan Zi1,2, Jie Gao1,2, Yun Mu1,2, Yidi Guan1,2, Zhen Cao1,2, Xitao Wang1,2, Qian Pei1,2, Yu Zeng1,2, Qi Fan1,2, Zimei Zeng1,2, Danmin Ou1,2, Jiang He1,2,3, Yingjie Nie8, Rong Tan1,2,3,4,5, Liang Weng1,2,3,4,5, Yuhao Li9, Rong Xiang9, Yuezhen Deng10,11,12,13,14, Lunquan Sun15,16,17,18,19.
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.Entities:
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Year: 2022 PMID： 35277657 DOI： 10.1038/s41388-022-02259-0
Source DB: PubMed Journal: Oncogene ISSN： 0950-9232 Impact factor: 8.756