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

Xianxiong Chen,Liang Zhou,Qi Sun,Feng Leng,Jiaxing Song,Lifeng Tan,Zijie Su,Jiong Ning,Huifang Zhu,Huan Li,Desheng Lu,Sapna Sayed,Shanshan Liu,Ou Sha,Zhongyuan Wang

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.

Highlights

Breast cancer is one of the most common malignancies diagnosed in women globally
transmembrane protein 97 (TMEM97) could upregulate enhanced the transcriptional activity stimulated by either wild-type the expression of active β-catenin and total β-catenin in a dose-dependent manner (Fig. 3D). These results suggest TMEM97 promotes the association of LRP6 with CK1δ/ε that TMEM97 may potentiate LRP6-mediated Wnt signaling via the To determine the effect of TMEM97 on the interaction of LRP6 regulation of LRP6 phosphorylation
It has been reported that the recombinant Mesd protein and its C-terminal region peptide, two antagonists of LRP6, markedly suppressed Wnt/β-catenin signaling, cell proliferation and tumor growth in breast cancer [38]

Summary

Introduction

The advanced therapeutic approaches have significantly improved the clinical outcome, the recurrence and metastasis remain the leading cause in patients with breast cancer. Triple-negative breast cancer (TNBC), negative for estrogen receptor (ER), progesterone receptor (PR), and HER2, is the most aggressive subtype associated with poorer prognosis than other subtypes due to the lack of effective therapeutic targets [2]. The Wnt/β-catenin signaling pathway plays a key role in multiple cellular processes involved in embryonic development, stem cell maintenance, and tumorigenesis [3]. This pathway depends on stabilization of β-catenin, which is regulated by a destruction complex composed of casein kinase 1 (CK1), axis inhibitor (AXIN), glycogen synthase kinase-3 (GSK3β), and adenomatous polyposis coli (APC) [4]. Wnt/β-catenin signaling is activated when secreted Wnt ligands bind to their cell membrane receptors frizzled (Fzd) and low-density lipoprotein receptorrelated proteins 5/6 (LRP5/6), leading to phosphorylation of LRP5/

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Conclusion