EGF-induced nuclear localization of SHCBP1 activates β-catenin signaling and promotes cancer progression

  • Oncogene. 2019 Jan;38(5):747-764. doi: 10.1038/s41388-018-0473-z.
Lei Liu  1  2 ,  Yi Yang  3  4 ,  Shihua Liu  1  2 ,  Tianyu Tao  1  2 ,  Junchao Cai  1  2 ,  Jueheng Wu  1  2 ,  Hongyu Guan  5 ,  Xun Zhu  1  6 ,  Zhenjian He  1  7 ,  Jun Li  1  8 ,  Erwei Song  9 ,  Musheng Zeng  10 ,  Mengfeng Li  11  12
Affiliations
  • 1. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China.
  • 2. Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 3. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China. [email protected].
  • 4. Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. [email protected].
  • 5. Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 6. Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong, China.
  • 7. School of Public-Health, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 8. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 9. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 10. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 11. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China. [email protected].
  • 12. Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. [email protected].
PMID: 30177836 DOI: 10.1038/s41388-018-0473-z
Abstract

Aberrant activation of EGFR represents a common event in non-small cell lung carcinoma (NSCLC) and activates various downstream signaling pathways. While EGFR activation of β-catenin signaling was previously reported, the mediating mechanism remains unclear. Our current study found that EGFR activation in NSCLC cells releases SHC-binging protein 1 (SHCBP1) from SHC adaptor protein 1 (SHC1), which subsequently translocates into the nucleus and directly promotes the transactivating activity of β-catenin, consequently resulting in development of NSCLC cell stemness and malignant progression. Furthermore, SHCBP1 promotes β-catenin activity through enhancing the CBP/β-catenin interaction, and most interestingly, a candidate drug that blocks the CBP/β-catenin binding effectively abrogates the aforementioned biological effects of SHCBP1. Clinically, SHCBP1 level in NSCLC tumors was found to inversely correlate with patient survival. Together, our study establishes a novel convergence between EGFR and β-catenin pathways and highlights a potential significance of SHCBP1 as a prognostic biomarker and a therapeutic target.

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