KLF12 transcriptionally regulates <i>PD‐L1</i> expression in non‐small cell lung cancer

Abstract

Recent studies have pointed to the role of Krüpple‐like factor 12 (KLF12) in cancer‐associated processes, including cancer proliferation, apoptosis, and metastasis. However, the role of KLF12 in tumor immunity remains obscure. Here, we found that KLF12 expression was significantly higher in non‐small cell lung cancer (NSCLC) cells with higher programmed death‐ligand 1 ( PD‐L1 ) expression. Additionally, a positive correlation between KLF12 and PD‐L1 was observed in clinical patient tumor tissues. By chromatin immunoprecipitation (ChIP) analysis, KLF12 was identified to bind to the CACCC motif of the PD‐L1 promoter. Overexpression of KLF12 promoted PD‐L1 transcription, whereas silencing of KLF12 inhibited PD‐L1 transcription. Furthermore, signal transducer and activator of transcription 1 (STAT1)‐ and STAT3‐triggered PD‐L1 transcription was abolished in the absence of KLF12 , and KLF12 knockdown weakened the binding of STAT1 and STAT3 to the PD‐L1 promoter. Mechanistically, KLF12 physically interacted with P300, a histone acetyltransferase. In addition, KLF12 silencing reduced P300 binding to the PD‐L1 promoter, which subsequently caused decreased acetylation of histone H3. PD‐L1 transcription driven by KLF12 overexpression was eliminated by EP300 silencing. In immunocompetent mice, KLF12 knockout inhibited tumor growth and promoted infiltration of CD8 + T cells. However, this phenomenon was not observed in immunodeficient mice. Overall, this study reveals KLF12‐mediated transcriptional regulation of PD‐L1 in NSCLC; targeting KLF12 may be a potential therapeutic strategy for NSCLC.