The novel transcription factor BTNL9 represses the cell cycle progression and DNA replication independently of p53 regulation in non-small-cell lung cancer

BTNL9 (butyrophilin-like 9), an immune-regulating BTN/BTNL family member, has shown an emerging yet underexplored role in cancer biology. Our study uncovers a novel role for BTNL9 as a novel transcription factor, independent of its known immunological functions. ChIP-seq analysis reveals its capacity to bind to the promoter regions, shedding light on a potential regulatory network. RNA-seq and western blot analyses reveal that BTNL9 engages in tumor-suppressive activities, inhibiting cell cycle progression and DNA replication, and regulating a subset of p53-regulated genes in a p53-independent manner. Our xenograft mouse model discloses BTNL9's potent tumor-suppressing capabilities. Moreover, TCGA database mining discovers that higher BTNL9 expression correlates with improved complete remission rates following primary treatment in lung cancer patients. Additionally, BTNL9 overexpression is associated with increased immune cell infiltration including Tfh cells, activated B cells, macrophages, CD8+ T cells, and NK cells. Collectively, our study identifies BTNL9 as a multifaceted transcription factor with significant implications in cancer biology and therapy.