KLF9 suppresses gastric cancer cell invasion and metastasis through transcriptional inhibition of MMP28

Gastric cancer (GC) is among the most lethal human malignancies, and the leading cause of GC mortality is metastasis. However, the precise mechanism of GC metastasis remains unclear. To screen key transcriptional factors (TFs) involved in GC metastasis, we performed bioinformatics analysis of The Cancer Genome Atlas database and found that Krüppel-like factor 9 (KLF9) is a GC metastasis-associated TF. KLF9 is significantly decreased in patients with GC with distant metastasis compared with those patients without distant metastasis. Ectopic expression of KLF9 evidently inhibited the migration and invasion capabilities of GC cells. Conversely, knockdown of KLF9 endowed GC cells with stronger invasive capacity. Moreover, tail intravenous injection confirmed that KLF9 strongly inhibits the lung metastasis process of GC in vivo. Mechanistically, chromatin immunoprecipitation coupled with high-throughput sequencing data from Encyclopedia of DNA Elements revealed that KLF9 specifically binds to the promoter region of matrix metalloproteinase (MMP)28. Further quantitative real-time PCR and dual-luciferase assay indicated that KLF9 directly inhibited MMP28 transcription. Importantly, decreased invasion and metastasis capability of GC cells caused by ectopic KLF9 expression could be rescued via reinforcing MMP28 expression in vivo. Collectively, our study indicates that KLF9 significantly suppresses GC cell invasion and metastasis through inhibiting MMP28 transcription.—Li, Y., Sun, Q., Jiang, M., Li, S., Zhang, J., Xu, Z., Guo, D., Gu, T., Wang, B., Xiao, L., Zhou, T., Zhuo, W. KLF9 suppresses gastric cancer cell invasion and metastasis through transcriptional inhibition of MMP28. FASEB J. 33, 7915–7928 (2019). www.fasebj.org