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Aberrant expression of sperm-associated antigen 5 (SPAG5) is implicated to play oncogenic roles in several types of cancers. However, the functions of SPAG5 in lung adenocarcinoma remain unclear. In this study, we investigated the role of SPAG5 in lung adenocarcinoma. We found that SPAG5 was upregulated in most of the lung adenocarcinoma cell lines as compared to normal lung epithelial cells. SPAG5 knockdown suppressed proliferation, colony forming, and migration of lung adenocarcinoma A549 cells in vitro and inhibited tumor growth in vivo. These suggest that upregulated SPAG5 promotes lung tumor progression. Importantly, treatment with MDM2 inhibitor, Nutlin-3a, restored p53 and p21 expression and suppressed SPAG5 expression in wild-type p53 lung adenocarcinoma cells, A549 and H460, but not in p53-null lung cancer cells, H1299. This suggests that the p53 signal pathway is essential for SPAG5 suppression. In addition, knocking-down p53 or p21 in A549 and H460 cells attenuated Nutlin-3a-induced repression of SPAG5, which further supports that the p53-p21 axis is required for SPAG5 repression. Thus, SPAG5 can serve as a prognostic marker, and therapeutic strategy targeting the p53-p21-SPAG5 axis may have important clinical implications. • SPAG5 is upregulated in lung adenocarcinoma. • SPAG5 knockdown suppresses proliferation, colony forming, and migration. • SPAG5 is regulated in a p53-and p21-dependent manner. • SPAG5 can be a prognostic marker and therapeutic target for lung adenocarcinoma. [ABSTRACT FROM AUTHOR]