PUBLICATION
SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling
- Authors
- Rong, Z., Zhang, L., Li, Z., Xiao, Z., Duan, Y., Ren, X., Zi, Y., Gao, J., Mu, Y., Guan, Y., Cao, Z., Wang, X., Pei, Q., Zeng, Y., Fan, Q., Zeng, Z., Ou, D., He, J., Nie, Y., Tan, R., Weng, L., Li, Y., Xiang, R., Deng, Y., Sun, L.
- ID
- ZDB-PUB-220315-9
- Date
- 2022
- Source
- Oncogene 41(16): 2390-2403 (Journal)
- Registered Authors
- Li, Yuhao
- Keywords
- none
- 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
- PubMed
- 35277657 Full text @ Oncogene
Citation
Rong, Z., Zhang, L., Li, Z., Xiao, Z., Duan, Y., Ren, X., Zi, Y., Gao, J., Mu, Y., Guan, Y., Cao, Z., Wang, X., Pei, Q., Zeng, Y., Fan, Q., Zeng, Z., Ou, D., He, J., Nie, Y., Tan, R., Weng, L., Li, Y., Xiang, R., Deng, Y., Sun, L. (2022) SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling. Oncogene. 41(16):2390-2403.
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.
Errata / Notes
Correction: https://www.nature.com/articles/s41388-022-02374-y Corrects: https://www.nature.com/articles/s41388-022-02259-0
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping