Dual-specific phosphatase 5 (DUSP5), upregulated in lung adenocarcinoma, as a potential therapeutic target for lung...

Dual specific phosphatases (DUSPs) are a family of phosphatases, including DUSP4, DUSP5, and DUSP6, that function as negative regulators of the RAF/MEK/ERK pathway. These DUSPs have been extensively studied in various human cancers, particularly those with KRAS mutations. Our previous research indicated that these DUSPs are downregulated by KRAS knockdown in KRAS mutant lung cancer cell lines and upregulated in an hTERT/Cdk4-immortalized normal human bronchial cell line HBEC3-KT expressing mutant KRAS^V12, suggesting their important roles in lung cancer. Thus, this study aims to investigate the role of DUSP5, which has been the least investigated among those DUSPs, in lung cancer. DUSP5 was upregulated upon inducible expression of KRAS^V12 in HBEC3-KT. Increased DUSP5 expression was observed in adenocarcinoma patients, particularly those with KRAS mutations, and was correlated with shorter overall survival. Intriguingly, DUSP5 was increased in patients with mutant KRAS but not in those with mutant EGFR or BRAF, suggesting mutant KRAS-specific upregulation of DUSP5. Supporting this finding, expression of mutant EGFR or BRAF did not affect DUSP5 expression in HBEC3-KT. However, the KRAS mutant-specific DUSP5 upregulation was not observed in lung cancer cell lines. DUSP5 silencing suppressed proliferation and both anchorage-independent and dependent colony formation. DUSP5 silencing-induced growth suppression was partially due to G1 cell cycle arrest, associated with p21 upregulation. Collectively, our findings highlight DUSP5 as a potential therapeutic target for lung cancer.