FOXM1/NCAPH activates glycolysis to promote colon adenocarcinoma stemness and 5-FU resistance

Chemotherapy using 5-fluorouracil (5-FU) is currently considered the most effective treatment for advanced colon adenocarcinoma (COAD). However, drug resistance remains a major obstacle in treating COAD. Non-SMC condensin I complex subunit H (NCAPH) is known to have a certain impact on the development of COAD, but its precise involvement in the mechanism of 5-FU resistance has not been demonstrated. Bioinformatics analysis was utilized to assay the expression of NCAPH and Forkhead box M1 (FOXM1) in COAD tumor tissues, which was then verified in COAD cell lines. The resistance of COAD cells to 5-FU was measured by CCK-8 assay, stemness was tested by cell sphere formation assay, and glycolysis ability was measured by cellular energy analysis metabolism. Chromatin Immunoprecipitation and dual-luciferase reporter assays were done to confirm the specific interaction between FOXM1 and NCAPH. The expression levels of FOXM1 and NCAPH were significantly upregulated in COAD tissues and cells, and they were involved in regulating the glycolytic signaling pathway. Inhibition of the glycolytic pathway could reverse the effect of NCAPH overexpression on COAD stemness and resistance. FOXM1 was identified as a transcription factor of NCAPH, and it regulated COAD glycolysis, cell stemness, and 5-FU resistance by activating NCAPH expression. FOXM1-mediated upregulation of NCAPH expression promoted COAD cell stemness and resistance via the glycolytic pathway. This study provides a possible mechanism for the FOXM1/NCAPH axis in the glycolytic pathway, cell stemness, and resistance in COAD.

[1]  Linhong Liao,et al.  Non-SMC condensin I complex subunit H promotes the malignant progression and cisplatin resistance of breast cancer MCF-7 cells , 2022, Oncology letters.

[2]  Xiangmin Yang,et al.  KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism , 2022, International journal of molecular sciences.

[3]  Yan Wang,et al.  NCAPH regulates gastric cancer progression through DNA damage response. , 2021, Neoplasma.

[4]  W. Qiu,et al.  The cross-talk between tumor cells and activated fibroblasts mediated by lactate/BDNF/TrkB signaling promotes acquired resistance to anlotinib in human gastric cancer , 2021, Redox biology.

[5]  Yong Duan,et al.  miR-133b targets NCAPH to promote β-catenin degradation and reduce cancer stem cell maintenance in non-small cell lung cancer , 2021, Signal Transduction and Targeted Therapy.

[6]  L. Du,et al.  HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness , 2021, Cancer Research.

[7]  Dan Xu,et al.  FoxM1 promotes Wnt/β‐catenin pathway activation and renal fibrosis via transcriptionally regulating multi‐Wnts expressions , 2021, Journal of cellular and molecular medicine.

[8]  Chunying Shi,et al.  Identification of NCAPH as a biomarker for prognosis of breast cancer , 2020, Molecular Biology Reports.

[9]  J. Shao,et al.  NCAPH is upregulated in endometrial cancer and associated with poor clinicopathologic characteristics , 2020, Annals of human genetics.

[10]  S. Park,et al.  NCAPH Is Required for Proliferation, Migration and Invasion of Non-small-cell Lung Cancer Cells , 2020, AntiCancer Research.

[11]  F. Fang,et al.  MiR-138 Suppresses the PDK1 Expression to Decrease the Oxaliplatin Resistance of Colorectal Cancer , 2020, OncoTargets and therapy.

[12]  S. Richard,et al.  CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis–Driven Hepatocarcinogenesis via ERK‐Dependent PKM2 Nuclear Relocalization and Activation , 2020, Hepatology.

[13]  Zheng Xu,et al.  FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A , 2020, Cancer cell international.

[14]  A. Jemal,et al.  Colorectal cancer statistics, 2020 , 2020, CA: a cancer journal for clinicians.

[15]  W. Dai,et al.  SIK2 Promotes Cisplatin Resistance Induced by Aerobic Glycolysis in Breast Cancer Cells through PI3K/AKT/mTOR Signaling Pathway. , 2020, Bioscience reports.

[16]  Jia Shi,et al.  PKM2 regulates angiogenesis of VR‐EPCs through modulating glycolysis, mitochondrial fission, and fusion , 2020, Journal of cellular physiology.

[17]  W. Dai,et al.  Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis , 2020, Journal of Experimental & Clinical Cancer Research.

[18]  Yiyan Lei,et al.  HIF-1ɑ-regulated miR-1275 maintains stem cell-like phenotypes and promotes the progression of LUAD by simultaneously activating Wnt/β-catenin and Notch signaling , 2020, Theranostics.

[19]  Y. Ba,et al.  Exosome‐delivered circRNA promotes glycolysis to induce chemoresistance through the miR‐122‐PKM2 axis in colorectal cancer , 2020, Molecular oncology.

[20]  T. Sasahira,et al.  Non-SMC Condensin I Complex Subunit H (NCAPH) Is Associated with Lymphangiogenesis and Drug Resistance in Oral Squamous Cell Carcinoma , 2019, Journal of clinical medicine.

[21]  Jia-geng Zhu,et al.  FOXM1 contributes to docetaxel resistance in castration-resistant prostate cancer by inducing AMPK/mTOR-mediated autophagy. , 2019, Cancer letters.

[22]  Kyung-tae Kim,et al.  Non-SMC condensin I complex subunit H mediates mature chromosome condensation and DNA damage in pancreatic cancer cells , 2019, Scientific Reports.

[23]  Jonathan J. West,et al.  Stem cell-like breast cancer cells with acquired resistance to metformin are sensitive to inhibitors of NADH-dependent CtBP dimerization. , 2019, Carcinogenesis.

[24]  Z. Stadler,et al.  Immunotherapy in colorectal cancer: rationale, challenges and potential , 2019, Nature Reviews Gastroenterology & Hepatology.

[25]  E. Lam,et al.  FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression , 2019, Scientific Reports.

[26]  D M Parkin,et al.  Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods , 2018, International journal of cancer.

[27]  B. Baradaran,et al.  MicroRNAs and breast cancer stem cells: Potential role in breast cancer therapy , 2018, Journal of cellular physiology.

[28]  M. Shen,et al.  Prostate Stem Cells and Cancer Stem Cells. , 2018, Cold Spring Harbor perspectives in medicine.

[29]  Maria C. Lecca,et al.  Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer , 2018, Nature Cell Biology.

[30]  Dong Wang,et al.  Effect of pyruvate kinase M2-regulating aerobic glycolysis on chemotherapy resistance of estrogen receptor-positive breast cancer , 2018, Anti-cancer drugs.

[31]  S. Sajdak,et al.  Ovarian cancer stem cells: A target for oncological therapy. , 2018, Advances in clinical and experimental medicine : official organ Wroclaw Medical University.

[32]  N. Teng,et al.  Targeting FOXM1 Improves Cytotoxicity of Paclitaxel and Cisplatinum in Platinum-Resistant Ovarian Cancer , 2017, International Journal of Gynecologic Cancer.

[33]  J. Lathia,et al.  Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications , 2017, Neurotherapeutics.

[34]  Lunquan Sun,et al.  The FOXM1–ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells , 2017, Cell Death & Disease.

[35]  Q. Kong,et al.  NCAPH plays important roles in human colon cancer , 2017, Cell Death & Disease.

[36]  K. L. Silva,et al.  FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance. , 2015, Cellular signalling.

[37]  G. J. Yoshida.  Metabolic reprogramming: the emerging concept and associated therapeutic strategies , 2015, Journal of experimental & clinical cancer research : CR.

[38]  Min Su,et al.  Cancer stem cells in progression of colorectal cancer , 2015, Oncotarget.

[39]  M. Provinciali,et al.  Identification and Characterization of Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma Cell Lines , 2015, Cellular Physiology and Biochemistry.

[40]  R. Tuli,et al.  Review of systemic therapies for locally advanced and metastatic rectal cancer. , 2015, Journal of gastrointestinal oncology.

[41]  R. James,et al.  Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial , 2000, The Lancet.

[42]  A. Gartel,et al.  Nuclear FOXM1 drives chemoresistance in AML , 2017, Leukemia.

[43]  F. Lévi,et al.  Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.