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

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.

Keywords

Colorectal cancer / KRAS mutation / KLF5 / oxaliplatin / chemotherapy resistance

References

[1] Siegel RL,Jemal A.Cancer statistics, 2024.CA Cancer J Clin2024;74:12-49

[2] Biller LH.Diagnosis and treatment of metastatic colorectal cancer: a review.JAMA2021;325:669-85

[3] Bando H,Yoshino T.Therapeutic landscape and future direction of metastatic colorectal cancer.Nat Rev Gastroenterol Hepatol2023;20:306-22

[4] Xu Z,Zhang Y.CCL7 and TGF-β secreted by MSCs play opposite roles in regulating CRC metastasis in a KLF5/CXCL5-dependent manner.Mol Ther2022;30:2327-41 PMCID:PMC9171262

[5] Takeda T,Takahashi H.A stem cell marker KLF5 regulates CCAT1 via three-dimensional genome structure in colorectal cancer cells.Br J Cancer2022;126:109-19 PMCID:PMC8727571

[6] Shen X,Xu Z.KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response.Cell Death Dis2022;13:303 PMCID:PMC8980070

[7] Zhou J,Zhang Z.Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma.Gut2022;71:665-75 PMCID:PMC8921580

[8] Zhang B,Mai F.Interruption of KLF5 acetylation promotes PTEN-deficient prostate cancer progression by reprogramming cancer-associated fibroblasts.J Clin Invest2024;134:e175949 PMCID:PMC11245161

[9] Wu Y,Shao Y.KLF5 promotes tumor progression and parp inhibitor resistance in ovarian cancer.Adv Sci2023;10:e2304638 PMCID:PMC10625120

[10] Tang Y,Zhu J.Positive feedback regulation between KLF5 and XPO1 promotes cell cycle progression of basal like breast cancer.Adv Sci2025;12:e2412096 PMCID:PMC12021099

[11] Yuan M,Chen S.PDP1 promotes KRAS mutant colorectal cancer progression by serving as a scaffold for BRAF and MEK1.Cancer Lett2024;597:217007

[12] Yu J,Sang Q.Super-enhancer activates master transcription factor NR3C1 expression and promotes 5-FU resistance in gastric cancer.Adv Sci2025;12:e2409050 PMCID:PMC11831572

[13] Jiang YY,Li CQ.TP63, SOX2, and KLF5 establish a core regulatory circuitry that controls epigenetic and transcription patterns in esophageal squamous cell carcinoma cell lines.Gastroenterology2020;159:1311-27.e19

[14] Wu Q,Gao Z.KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8⁺ T-cell-dependent antitumor immunity.Theranostics2023;13:1381-400 PMCID:PMC10008740

[15] Garnett MJ,Heidorn SJ.Systematic identification of genomic markers of drug sensitivity in cancer cells.Nature2012;483:570-5 PMCID:PMC3349233

[16] Zhu G,Xia H,Bi F.Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer.Mol Cancer2021;20:143 PMCID:PMC8571891

[17] Loriot Y,Deutsch E,Soria JC.Are RAS mutations predictive markers of resistance to standard chemotherapy?.Nat Rev Clin Oncol2009;6:528-34

[18] Song P,Bao Y.Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy.J Hematol Oncol2024;17:46 PMCID:PMC11184729

[19] Franklin JM,Guan KL.Insights into recent findings and clinical application of YAP and TAZ in cancer.Nat Rev Cancer2023;23:512-25

[20] Goel S,Zhao JJ.Targeting CDK4 and CDK6 in cancer.Nat Rev Cancer2022;22:356-72 PMCID:PMC9149100

[21] Hata AN,Faber AC.The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics.Cancer Discov2015;5:475-87 PMCID:PMC4727530

[22] Lin YF,Chang CK.Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies.J Clin Invest2013;123:3861-75 PMCID:PMC3754255

[23] Shan J,Zhang Q,Liu Z.Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer.Protein Cell2016;7:571-85 PMCID:PMC4980335

[24] Banerjee S,Padhye S.Structure-activity studies on therapeutic potential of thymoquinone analogs in pancreatic cancer.Pharm Res2010;27:1146-58 PMCID:PMC3093961

[25] Tsubaki M,Matsuda T.Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy.Cancer Cell Int2023;23:73 PMCID:PMC10108455

[26] Liu F,Villa GR.EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling.Mol Cell2015;60:307-18 PMCID:PMC4609298

[27] Morgan MP,Das S.The role of transcription factors in the acquisition of the four latest proposed hallmarks of cancer and corresponding enabling characteristics.Semin Cancer Biol2022;86:1203-15

[28] Chen Z,Ding Y.YD277 suppresses triple-negative breast cancer partially through activating the endoplasmic reticulum stress pathway.Theranostics2017;7:2339-49 PMCID:PMC5505065

[29] Kim J,de Sabando AR.The novel small-molecule SR18662 efficiently inhibits the growth of colorectal cancer in vitro and in vivo.Mol Cancer Ther2019;18:1973-84 PMCID:PMC6825545

[30] Huang H,Chen Z.ML264 inhibits osteosarcoma growth and metastasis via inhibition of JAK2/STAT3 and WNT/β-catenin signalling pathways.J Cell Mol Med2020;24:5652-64 PMCID:PMC7214147

[31] Zhang Z,He J.Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells.Cell Death Dis2025;16:28 PMCID:PMC11743205

[32] Poluri RTK,Allain ÉP.KLF5 and NFYA factors as novel regulators of prostate cancer cell metabolism.Endocr Relat Cancer2021;28:257-71

[33] Yang Y,Jarmel MH,Katz JP.p53 mutation alters the effect of the esophageal tumor suppressor KLF5 on keratinocyte proliferation.Cell Cycle2012;11:4033-9 PMCID:PMC3507498

[34] Yang Y,Tetreault MP.Loss of transcription factor KLF5 in the context of p53 ablation drives invasive progression of human squamous cell cancer.Cancer Res2011;71:6475-84 PMCID:PMC3193554

[35] Lu Y,Tanikawa C.Large-scale genome-wide association study of East Asians identifies loci associated with risk for colorectal cancer.Gastroenterology2019;156:1455-66 PMCID:PMC6441622

[36] Liao Q,Zhang N.Network analysis of KLF5 targets showing the potential oncogenic role of SNHG12 in colorectal cancer.Cancer Cell Int2020;20:439 PMCID:PMC7487661