Correlation between KAT6A and PD-L1 expression and role of KAT6A in colorectal cancer

Abstract

BACKGROUND

Immune checkpoint inhibitors (ICIs) are effective cancer treatments; however, a significant proportion of colorectal cancer (CRC) patients exhibit limited responses to ICI therapy. KAT6A has been strongly associated with cancer initiation and progression.

AIM

To examine the role of KAT6A in CRC progression and immune evasion.

METHODS

The functional role of KAT6A was evaluated through genetic knockdown, pharmacological inhibition (WM-3835), and CRISPR/dCas9-mediated epigenetic editing in CRC cells. T cell-mediated apoptosis was assessed using co-culture models, and H3K23pr was measured via chromatin immunoprecipitation assays. PD-L1 expression at mRNA and protein levels was analyzed under KAT6A knockdown conditions.

RESULTS

KAT6A suppression reduced CRC cell proliferation, invasion, and migration. Pharmacological or epigenetic disruption of KAT6A phenocopied these effects, with dose-dependent reductions in H3K23pr (28.4% residual at 10 μM) and PD-L1 expression. KAT6A knockdown enhanced T cell-mediated apoptosis, evidenced by increased expression of granzyme B and perforin. Mechanistically, KAT6A loss decreased H3K23pr and reduced RNA polymerase II occupancy on the PD-L1 promoter, leading to suppressed PD-L1 transcription. CRISPR/dCas9-mediated H3K23pr editing at the PD-L1 promoter directly modulated immune evasion, confirming its causal role. Overexpression of PD-L1 mitigated the inhibitory effects of KAT6A knockdown on CRC progression and immune evasion.

CONCLUSION

KAT6A drives CRC progression and immune evasion by promoting histone H3 propionylation to epigenetically activate PD-L1 expression. Targeting KAT6A or its downstream H3K23pr-PD-L1 axis represents a promising therapeutic strategy to overcome ICI resistance in CRC.

Keywords: Colorectal cancer; Epigenetic regulation; KAT6A; PD-L1; Immune evasion

Core Tip: KAT6A drives colorectal cancer (CRC) progression and immune evasion by promoting histone H3 propionylation to epigenetically activate PD-L1 expression. Targeting KAT6A or its downstream H3K23pr-PD-L1 axis represents a promising therapeutic strategy to overcome Immune checkpoint inhibitor resistance in CRC.