2. Academic Validation
  3. PCDH7 promotes EMT and chemoresistance by stabilizing ZEB1 via inhibition of TRIM26-mediated ubiquitination in lung adenocarcinoma

PCDH7 promotes EMT and chemoresistance by stabilizing ZEB1 via inhibition of TRIM26-mediated ubiquitination in lung adenocarcinoma

  • Biochem Pharmacol. 2026 Jan;243(Pt 2):117554. doi: 10.1016/j.bcp.2025.117554.
Sijie Chen 1,  Feixuan Li 1,  Liuzhen Meng 2,  Yu Li 1,  Zhangrong Xie 1,  Yuhao Cui 1,  Beisi Han 1,  Wenyu Li 1,  Zhiqing Zhou 1,  Xiaoniu He 3,  Shengmin Hu 4,  Guoan Chen 5
Affiliations

Affiliations

  • 1 Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
  • 2 Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 3 Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi 030032, China.
  • 4 Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 5 Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China. Electronic address: [email protected].
PMID: 41271034 DOI: 10.1016/j.bcp.2025.117554
Abstract

Cisplatin-based chemotherapy is the first-line treatment for lung adenocarcinoma (LUAD), but its effectiveness is often limited by drug resistance, which is commonly associated with epithelial-mesenchymal transition (EMT). Protocadherin-7 (PCDH7), a cell-surface Cadherin superfamily protein, has been linked to tumor growth and treatment resistance in various cancers; however, its role in LUAD cisplatin resistance remains unclear. Here, we report that the PCDH7 level is significantly increased in LUAD tissues, and high PCDH7 expression is associated with aggressive tumor characteristics, as shown by public microarray and RNA-seq data. PCDH7 silencing significantly reduces tumor cell proliferation, migration, and invasion, and notably enhances sensitivity to cisplatin in vitro. Knockdown of PCDH7 also suppressed tumor growth and metastasis in vivo while simultaneously potentiating the inhibitory effect of cisplatin on drug-resistant tumors. Mechanistically, PCDH7 physically interacts with ZEB1 and protects ZEB1 from ubiquitin-mediated proteasomal degradation by the E3 Ligase TRIM26. This PCDH7-mediated stabilization of ZEB1 maintains repression of E-cadherin and promotes EMT, ultimately leading to cisplatin resistance. Conversely, PCDH7 depletion restored ZEB1 ubiquitination and degradation, upregulated E-cadherin, reversed EMT, and re-sensitized cells to cisplatin-induced cell death. Our findings identify the PCDH7-ZEB1 axis as a key driver of EMT and chemoresistance in LUAD, highlighting it as a promising therapeutic target for overcoming cisplatin resistance and suppressing tumor metastatic progression.

Keywords

DDP; EMT; LUAD; PCDH7; TRIM26; Ubiquitination; ZEB1.

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