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

Zhuoxian Rong1,2,3,4,5, Lu Zhang1,2, Zhi Li1,2,3,4,5

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

Oncogene
|March 12, 2022
PubMed

Insights

Salt-inducible kinase 2 (SIK2) drives breast cancer stemness and Wnt/β-catenin activation. Inhibiting SIK2 reduces cancer recurrence and metastasis, offering a new therapeutic strategy for breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Breast cancer stem cells (BCSCs) drive tumor recurrence and metastasis.
  • Current therapies are ineffective against BCSCs.
  • Identifying novel targets for BCSCs is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate the role of Salt-inducible kinase 2 (SIK2) in maintaining breast cancer stemness.
  • To elucidate the molecular mechanism by which SIK2 regulates BCSCs.
  • To evaluate SIK2 inhibitors as a potential therapeutic strategy against breast cancer.

Main Methods:

  • High-throughput screening to identify SIK2 involvement in breast cancer stemness.
  • SIK2 knockdown experiments in breast cancer cells.
  • Western blotting to assess protein phosphorylation and signaling pathway activation (Wnt/β-catenin).
  • Treatment with SIK2 inhibitors (ARN-3236 and HG-9-91-01).
  • Analysis of IDH1 expression and metabolic reprogramming.

Main Results:

  • SIK2 is upregulated in recurrent breast cancer samples and promotes stemness.
  • SIK2 knockdown reduces the proportion of BCSCs and tumor initiation.
  • SIK2 directly phosphorylates LRP6, activating the Wnt/β-catenin pathway.
  • SIK2 inhibitors block LRP6 phosphorylation, reduce β-catenin, and impair stemness.
  • SIK2-activated Wnt/β-catenin signaling induces IDH1, leading to metabolic reprogramming.

Conclusions:

  • SIK2 is a key regulator of breast cancer stemness via Wnt/β-catenin pathway activation.
  • SIK2 inhibition disrupts CSC maintenance and metabolic reprogramming.
  • Targeting SIK2 represents a promising therapeutic approach for eliminating BCSCs and preventing recurrence.

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