# KLF5 promotes tumor proliferation and oxaliplatin resistance via chromatin remodeling in KRAS-mutated colorectal cancer

## TL;DR

This study shows that KLF5 helps KRAS-mutated colorectal cancer grow and resist chemotherapy, suggesting targeting KLF5 could improve treatment.

## Contribution

The study identifies KLF5 as a driver of proliferation and chemoresistance in KRAS-mutated CRC through chromatin remodeling.

## Key findings

- KLF5 upregulation is linked to enhanced proliferation and oxaliplatin resistance in KRAS-mutated CRC.
- KLF5 promotes chemoresistance via CDK4/6-Cyclin D1, stemness markers, and anti-apoptotic pathways.
- Targeting KLF5 could improve chemotherapy response in KRAS-mutated CRC.

## Abstract

Aim: Patients with KRAS-mutated colorectal cancer (CRC) frequently exhibit resistance to conventional chemotherapy and epidermal growth factor receptor (EGFR)-targeted therapies. This study investigates the role of the transcription factor KLF5 in mediating proliferation and chemoresistance in KRAS-mutated CRC, aiming to identify novel therapeutic strategies to improve treatment outcomes.

Methods: We analyzed the association between KLF5 expression, KRAS mutation status, and patient prognosis using CRC tissue microarrays and public datasets. Proliferative capacity and oxaliplatin sensitivity were compared between KRAS-mutated and wild-type patient-derived organoids. RNA sequencing and CUT&Tag sequencing were employed to assess KLF5-mediated chromatin accessibility and downstream transcriptional regulation in KRAS-mutated CRC cells. In vitro and in vivo functional studies were conducted using three pairs of KRAS-mutated CRC cell lines (with KLF5 knockdown or overexpression) to evaluate KLF5’s impact on proliferation, cell cycle progression, stemness, and oxaliplatin response.

Results: KRAS-mutated CRC demonstrated enhanced proliferative capacity and oxaliplatin resistance, accompanied by KLF5 upregulation. In KRAS-mutated CRC cells, KLF5 promoted chromatin accessibility to initiate downstream transcription programs regulating cell cycle progression, platinum drug resistance, and apoptosis. Mechanistically, KLF5 drives oxaliplatin resistance by promoting proliferation through upregulation of the CDK4/6-Cyclin D1 axis, enhancing stemness via LGR5 and Nanog, and activating the XIAP/Bcl-2-dependent anti-apoptotic signaling pathway. In vivo experiments further confirmed that KLF5-overexpressing KRAS-mutated CRC tumors exhibited accelerated growth and reduced oxaliplatin sensitivity.

Conclusion: This study reveals that aberrantly elevated KLF5 promotes proliferation and chemoresistance in KRAS-mutated CRC. Targeting KLF5 represents a promising strategy to enhance chemotherapeutic response in this aggressive CRC subtype, offering a rationale for clinical translation.