Targeting the PBX1–BCL2L1 Axis as a Therapeutic Strategy in Colorectal Cancer

Pre-B-cell leukemia homeobox 1 ( PBX1 ) is a transcription factor involved in diverse cellular processes, but its role in colorectal cancer (CRC) remains incompletely understood. In this study, we show that PBX1 is downregulated in CRC tissues and cell lines. Functional experiments revealed that PBX1 overexpression inhibits proliferation, migration, and invasion, but paradoxically suppresses apoptosis, suggesting a dual regulatory role. Transcriptome and CUT&Tag profiling identified BCL2L1 as a direct transcriptional target of PBX1. PBX1 binds the BCL2L1 promoter and enhances Bcl-xL expression, contributing to apoptotic resistance. BCL2L1 knockdown reversed the anti-apoptotic effects of PBX1 and restored apoptosis levels. Upon 5-fluorouracil (5-FU) treatment, PBX1 overexpression reduced cell viability, while concurrent BCL2L1 knockdown significantly enhanced drug sensitivity. In vivo, xenograft experiments demonstrated that PBX1 overexpression suppressed tumor growth, which was further augmented by BCL2L1 knockdown. These results underscore the dual role of PBX1 in simultaneously inhibiting tumor growth while promoting cell survival through the BCL2L1 –Bcl-xL axis. Targeting this pathway could offer a novel therapeutic strategy for enhancing CRC treatment efficacy by simultaneously inhibiting proliferation and restoring apoptotic sensitivity.