CHAF1B drives lung squamous cell carcinoma progression by repressing SETD7

CHAF1B, a histone chaperone component of the chromatin assembly factor-1 complex, is overexpressed in multiple cancers and linked to tumor progression, but its role in lung squamous-cell carcinoma (LUSC) remained unclear. This study identifies CHAF1B as a critical oncogenic driver in LUSC through integrated bioinformatics, in vitro experiments, and in vivo models. Analysis of the GSE68793 LUSC dataset via weighted gene co-expression network analysis (WGCNA) highlighted CHAF1B as a top hub gene enriched in cell cycle regulation pathways. Immunohistochemistry of 126 LUSC tissues confirmed CHAF1B overexpression compared to adjacent normal tissues, with higher expression correlating significantly with advanced tumor stages and poor patient survival. Functional assays demonstrated that CHAF1B knockdown suppressed LUSC cell proliferation, induced S-phase cell cycle arrest, and reduced colony formation. In mouse xenograft models, CHAF1B silencing markedly inhibited tumor growth, underscoring its pro-tumorigenic role.

RNA sequencing of CHAF1B-depleted cells revealed SETD7, a histone lysine methyltransferase and tumor suppressor, as a key downstream target. CHAF1B was found to bind the SETD7 promoter, repressing its transcription. SETD7 upregulation upon CHAF1B knockdown reversed proliferative effects, while co-knockdown of SETD7 and CHAF1B restored cell viability. Clinical data further supported SETD7's tumor-suppressive role, as higher SETD7 expression correlated with improved survival in non-small cell lung cancer (NSCLC) patients. Mechanistically, CHAF1B competitively occupies the SETD7 promoter, blocking transcriptional activation without direct protein interaction. This repression likely disrupts SETD7-mediated pathways, such as p53 stabilization and KRAS degradation, which are critical for inhibiting oncogenic signaling.

CHAF1B's oncogenic function aligns with its known roles in chromatin assembly during DNA replication and repair. Its overexpression in LUSC may drive unchecked cell cycle progression and genomic instability. The study also highlights CHAF1B's clinical relevance, as its expression inversely correlates with survival across multiple cancers, including bladder, breast, and liver carcinomas. These findings position CHAF1B as a potential therapeutic target, particularly for LUSC, which lacks effective targeted therapies. Current treatments like immune checkpoint inhibitors benefit only a subset of patients, emphasizing the need for novel strategies. Targeting CHAF1B could reactivate SETD7 and restore tumor-suppressive pathways, offering a promising avenue for intervention.

Challenges remain in translating these insights into clinical applications. While CHAF1B inhibition suppresses tumor growth in preclinical models, systemic targeting may affect normal proliferating cells, given its role in DNA replication. Further research is needed to identify selective inhibitors or delivery methods that minimize off-target effects. Additionally, the interplay between CHAF1B and other epigenetic regulators warrants exploration to uncover combinatorial therapeutic approaches. The study underscores the importance of epigenetic dysregulation in LUSC and provides a framework for understanding how histone chaperones like CHAF1B contribute to carcinogenesis. By elucidating the CHAF1B-SETD7 axis, this work advances the molecular characterization of LUSC and opens new pathways for biomarker development and targeted therapy.

In summary, CHAF1B emerges as a central epigenetic driver in LUSC, promoting tumor progression through transcriptional repression of SETD7. Its overexpression correlates with aggressive disease and poor prognosis, while its knockdown impedes proliferation and tumor growth. These findings not only deepen the understanding of LUSC pathogenesis but also highlight CHAF1B as a viable therapeutic target. Future studies should focus on validating CHAF1B inhibitors in clinical settings and exploring synergies with existing therapies to improve outcomes for patients with this recalcitrant malignancy.