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

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.