2. Academic Validation
  3. Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer

Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer

  • Cell Death Dis. 2021 Oct 6;12(10):912. doi: 10.1038/s41419-021-04211-8.
Huifang Zhu  # 1,  Zijie Su  # 1 2,  Jiong Ning  # 1,  Liang Zhou 1,  Lifeng Tan 1,  Sapna Sayed 1,  Jiaxing Song 1,  Zhongyuan Wang 1,  Huan Li 1,  Qi Sun 1,  Shanshan Liu 1,  Ou Sha 3,  Feng Leng 1 4,  Xianxiong Chen 1,  Desheng Lu 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, 518055, Shenzhen, China.
  • 2 Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, 530021, Nanning, China.
  • 3 School of Dentistry, Shenzhen University Health Science Centre, Shenzhen University, 518060, Shenzhen, China.
  • 4 Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, MD, 20892-4255, USA.
  • 5 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, 518055, Shenzhen, China. delu@szu.edu.cn.
  • # Contributed equally.
PMID: 34615853 DOI: 10.1038/s41419-021-04211-8
Abstract

Upregulation of transmembrane protein 97 (TMEM97) has been associated with progression and poor outcome in multiple human cancers, including breast Cancer. Recent studies suggest that TMEM97 may be involved in the activation of the Wnt/β-catenin pathway. However, the molecular mechanism of TMEM97 action on Wnt/β-catenin signaling is completely unclear. In the current study, TMEM97 was identified as an LRP6-interacting protein. TMEM97 could interact with LRP6 intracellular domain and enhance LRP6-mediated Wnt signaling in a CK1δ/ε-dependent manner. The binding of TMEM97 to LRP6 facilitated the recruitment of CK1δ/ε to LRP6 complex, resulting in LRP6 phosphorylation at Ser 1490 and the stabilization of β-catenin. In breast Cancer cells, knockout of TMEM97 attenuated the Wnt/β-catenin signaling cascade via regulating LRP6 phosphorylation, leading to a decrease in the expression of Wnt target genes AXIN2, LEF1, and Survivin. TMEM97 deficiency also suppressed cell viability, proliferation, colony formation, migration, invasion, and stemness properties in breast Cancer cells. Importantly, TMEM97 knockout suppressed tumor growth through downregulating the Wnt/β-catenin signaling pathway in a breast Cancer xenograft model. Taken together, our results revealed that TMEM97 is a positive modulator of canonical Wnt signaling. TMEM97-mediated Wnt signaling is implicated in the tumorigenesis of breast Cancer, and its targeted inhibition may be a promising therapeutic strategy for breast Cancer.

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