SMARCD1 is a dual regulator of PD-L1 expression and cell proliferation facilitating tumor evasion

Abstract

Purpose: Cancer cells often evade immune responses by overexpressing immune checkpoint regulators, such as programmed cell death ligand 1 (PD-L1). Identifying targets that regulate PD-L1 is a promising approach for anti-tumor therapy.

Methods: Based on our previous CRISPR-Cas9 screening, we identified SMARCD1, a subunit of the mating-type switching/sucrose fermentation (SWI/SNF) complex, as a factor that promotes tumor evasion by inducing PD-L1-mediated immune checkpoint responses. Immunohistochemical staining (IHC) was used to assess SMARCD1 expression levels in colorectal cancer (CRC) and normal tissues. CRISPR-Cas9 technology was employed to generate SMARCD1 knockout (KO) cell lines. Western blotting and flow cytometry were used to evaluate PD-L1 expression. Cell proliferation, invasion, migration, and apoptosis were also assessed. A tumor model was established to examine the in vivo effects of SMARCD1. RNA-seq and ChIP-seq analyses were conducted to investigate the potential mechanisms.

Results: SMARCD1 was significantly upregulated in CRC tissues. In vitro, SMARCD1 regulated PD-L1 expression and significantly promoted tumor growth. The SWI/SNF inhibitor FHT-1015 reversed the effects of SMARCD1 knockout. Mechanistically, SMARCD1 may maintain chromatin accessibility at the PD-L1 transcriptional regulatory element and promote cancer cell proliferation via the PI3K-Akt signaling pathway.

Conclusion: SMARCD1 regulates PD-L1 transcription and facilitates tumor cell proliferation, making it a promising target for CRC treatment.

Keywords: Colorectal cancer; PD-L1; Proliferation; SMARCD1; SWI/SNF.