Research update from the MCM team (May 2024)


We continue to characterise lung cancer biomarkers identified in the MCM1 project. This update focuses on KLF5, a well-studied gene that has been implicated in several cancer types. KLF5 is a transcription factor, which is expressed across numerous organs and tissues.

Project: Mapping Cancer Markers

Published on: 13 May 2024

Terminology

- Transcription factor: A protein that controls the rate of transcription from DNA to RNA, by binding a particular sequence of DNA.

- Transcription: The process by which an RNA copy is made from a DNA sequence.

- Promoter elements: The DNA region where transcription is initiated.

- Sphingolipid: A type of lipid that contains a backbone sphingoid base.

- Trophoblast: A layer of cells that helps a developing embryo attach to the uterus, protects the embryo, and forms part of the placenta.

- Diabetic neuropathy: Nerve damage that is caused by diabetes.

- Diabetic cardiomyopathy: Changes in heart muscle tissue’s structure and function caused by diabetes.

- Lupus nephritis: Kidney disease caused by lupus, an autoimmune disease.

- Chronic obstrictove pulmonary disease (COPD): A group of diseases that cause airway blockage and breathing-related problems.

Background

Identifying molecular markers and their combination (signatures) enables us to detect disease earlier (diagnostic signatures) and stratify patients into subgroups based on disease progression patterns (prognostic signatures). The final group of markers helps identify which patients will benefit from specific treatment options (predictive signatures). The Mapping Cancer Markers project analyses data sets with millions of data points collected from patients with cancers to find such diagnostic, prognostic and predictive signatures.

Since November 2013, World Community Grid volunteers have donated over 905,700 CPU years to the project, helping analyse data on lung and ovarian cancer and sarcoma, much more thoroughly than otherwise possible. We are immensely grateful for this continued support.

Focusing on characterising the 26 top-scoring genes in lung cancer, we have already discussed VAMP1, FARP1, GSDMB, ADH6, IL13RA1, PCSK5, TLE3, and HSD17B11 in previous MCM updates. Here, we outline information on KLF5. 

KLF5 Research

 

KLF5 (Krueppel-like factor 5) is a transcription factor that activates the transcription of multiple genes (Uniprot). The importance of KLF5 in lung cancer is further strengthened since it also targets genes we have already discussed: VAMP1, IL13RA1, PCSK5 and TLE3.

KLF5 has been implicated in diverse biological processes, including blood vessel remodelling[1] and maintenance[2], sphingolipid metabolism and skin barrier function[3], cell response to stress[4,5], tooth formation in mice[6], embryo and trophoblast differentiation[7,8,9],, skeletal muscle differentiation[10], and stem cell self-renewal[9,11]. KLF5 is expressed across many organs and tissues (Figure 1). Studies have also suggested that KLF5 may be implicated in conditions such as diabetic nephropathy[12] and cardiomyopathy[13], renal fibrosis in lupus nephritis[14], protection from immune response in colitis[15], and airway inflammation in asthma[16]. 

Figure 1. KLF5 expression across different tissue types (Human Protein Atlas).

KLF5 is also upregulated in the airways of patients with chronic obstructive pulmonary disease (COPD) and may be involved in tissue remodelling in COPD[17]. Notably, studies have demonstrated that COPD and lung cancer are closely linked at a molecular level[18].

As was the case with the other genes we have presented so far, KLF5 was found to have a protective role in lung cancer (Figure 2A), which is especially strong for non-smokers (Figure 2B).

A

B

Figure 2. (A) Survival curves for lung cancer patients with low and high expression of KLF5 (KMplot), and (B) for non-smoking patients only.

We have also explored the association between KLF5 and other cancers. As shown in Figure 3, comparing cancer tissues with normal tissues, KLF5 is differentially expressed in all but one cancer examined (indicated by red text). Notably, KLF5 is upregulated in lung cancer as well as most other cancers, while it is downregulated in only 7 of the 22 cancers examined. Within the literature, KLF5 has a well-studied association with numerous cancer types, including ovarian cancer[19], stomach cancer[20], esophageal cancer[21], thyroid cancer[22], prostate cancer[23], endometrial cancer[24], pancreatic cancer[25], and recently also in lung cancer[26].

Figure 3. Expression of KLF5 in normal and cancer tissue for multiple cancer types. Red text represents a significant difference between expression in cancer tissue compared with normal tissue (TNMplot).

If you have any questions or comments, please leave them in this thread for us to answer!

WCG Team

References

  1. Li X, He Y, Xu Y, Huang X, Liu J, Xie M, Liu X. KLF5 mediates vascular remodeling via HIF-1α in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2016 Feb 15;310(4):L299-310. doi: 10.1152/ajplung.00189.2015. Epub 2015 Dec 23. PMID: 26702149.
  2. Ma D, Zheng B, Liu HL, Zhao YB, Liu X, Zhang XH, Li Q, Shi WB, Suzuki T, Wen JK. Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission. PLoS Biol. 2020 Aug 20;18(8):e3000808. doi: 10.1371/journal.pbio.3000808. PMID: 32817651; PMCID: PMC7462304.
  3. Lyu Y, Guan Y, Deliu L, Humphrey E, Frontera JK, Yang YJ, Zamler D, Kim KH, Mohanty V, Jin K, Mohanty V, Liu V, Dou J, Veillon LJ, Kumar SV, Lorenzi PL, Chen Y, McAndrews KM, Grivennikov S, Song X, Zhang J, Xi Y, Wang J, Chen K, Nagarajan P, Ge Y. KLF5 governs sphingolipid metabolism and barrier function of the skin. Genes Dev. 2022 Aug 25;36(13-14):822–42. doi: 10.1101/gad.349662.122. Epub ahead of print. PMID: 36008138; PMCID: PMC9480852.
  4. Yang Y, Bhargava D, Chen X, Zhou T, Dursuk G, Jiang W, Wang J, Zong Z, Katz SI, Lomberk GA, Urrutia RA, Katz JP. KLF5 and p53 comprise an incoherent feed-forward loop directing cell-fate decisions following stress. Cell Death Dis. 2023 May 2;14(5):299. doi: 10.1038/s41419-023-05731-1. PMID: 37130837; PMCID: PMC10154356.
  5. Li X, Chen D, Ouyang B, Wang S, Li Y, Li L, Zhu S, Zheng G. KLF5/MDM2 Axis Modulates Oxidative Stress and Epithelial-Mesenchymal Transition in Human Lens Epithelial Cells: The Role in Diabetic Cataract. Lab Invest. 2023 Nov;103(11):100226. doi: 10.1016/j.labinv.2023.100226. Epub 2023 Jul 31. PMID: 37532224.
  6. Fu J, Zhang X, Zheng H, Yang G, Chen Z, Yuan G. A WWP2-PTEN-KLF5 signaling axis regulates odontoblast differentiation and dentinogenesis in mice. J Biol Chem. 2022 Aug;298(8):102220. doi: 10.1016/j.jbc.2022.102220. Epub 2022 Jul 1. PMID: 35780838; PMCID: PMC9358474.
  7. Lin SC, Wani MA, Whitsett JA, Wells JM. Klf5 regulates lineage formation in the pre-implantation mouse embryo. Development. 2010 Dec;137(23):3953-63. doi: 10.1242/dev.054775. Epub 2010 Oct 27. PMID: 20980403; PMCID: PMC2976279.
  8. Kinisu M, Choi YJ, Cattoglio C, Liu K, Roux de Bezieux H, Valbuena R, Pum N, Dudoit S, Huang H, Xuan Z, Kim SY, He L. Klf5 establishes bi-potential cell fate by dual regulation of ICM and TE specification genes. Cell Rep. 2021 Nov 9;37(6):109982. doi: 10.1016/j.celrep.2021.109982. PMID: 34758315; PMCID: PMC8711565.
  9. Dou C, Wu L, Zhang J, He H, Xu T, Yu Z, Su P, Zhang X, Wang J, Miao YL, Zhou J. The transcriptional activator Klf5 recruits p300-mediated H3K27ac for maintaining trophoblast stem cell pluripotency. J Mol Cell Biol. 2024 Jan 5;15(7):mjad045. doi: 10.1093/jmcb/mjad045. PMID: 37533201; PMCID: PMC10768793.
  10. Hayashi S, Manabe I, Suzuki Y, Relaix F, Oishi Y. Klf5 regulates muscle differentiation by directly targeting muscle-specific genes in cooperation with MyoD in mice. Elife. 2016 Oct 15;5:e17462. doi: 10.7554/eLife.17462. PMID: 27743478; PMCID: PMC5074804.
  11. Parisi S, Passaro F, Aloia L, Manabe I, Nagai R, Pastore L, Russo T. Klf5 is involved in self-renewal of mouse embryonic stem cells. J Cell Sci. 2008 Aug 15;121(Pt 16):2629-34. doi: 10.1242/jcs.027599. Epub 2008 Jul 24. PMID: 18653541.
  12. Li Y, Sui X, Hu X, Hu Z. Overexpression of KLF5 inhibits puromycin‑induced apoptosis of podocytes. Mol Med Rep. 2018 Oct;18(4):3843-3849. doi: 10.3892/mmr.2018.9366. Epub 2018 Aug 9. PMID: 30106142; PMCID: PMC6131625.
  13. Kyriazis ID, Hoffman M, Gaignebet L, Lucchese AM, Markopoulou E, Palioura D, Wang C, Bannister TD, Christofidou-Solomidou M, Oka SI, Sadoshima J, Koch WJ, Goldberg IJ, Yang VW, Bialkowska AB, Kararigas G, Drosatos K. KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy. Circ Res. 2021 Feb 5;128(3):335-357. doi: 10.1161/CIRCRESAHA.120.316738. Epub 2020 Dec 2. PMID: 33539225; PMCID: PMC7870005.
  14. Tao S, Tan X, Chai W, Peng X, Zheng W, Fu R, Deng M. Knockdown of KLF5 ameliorates renal fibrosis in MRL/lpr mice via inhibition of MX1 transcription. Immun Inflamm Dis. 2023 Jul;11(7):e937. doi: 10.1002/iid3.937. PMID: 37506140; PMCID: PMC10373570.
  15. Shieh J, Chu TH, Liu Y, Kim J, Ruiz de Sabando A, Kobayashi S, Zee SY, Sheridan BS, Bialkowska AB, Yang VW. KLF5 protects the intestinal epithelium against Th17 immune response in a murine colitis model. JCI Insight. 2022 Apr 8;7(7):e153488. doi: 10.1172/jci.insight.153488. PMID: 35393949; PMCID: PMC9057631.
  16. Lin Z, Bao R, Niu Y, Kong X. KLF5-mediated pyroptosis of airway epithelial cells leads to airway inflammation in asthmatic mice through the miR-182-5p/TLR4 axis. Mol Immunol. 2024 Apr 8;170:9-18. doi: 10.1016/j.molimm.2024.03.007. Epub ahead of print. PMID: 38593669.
  17. Abe K, Sugiura H, Hashimoto Y, Ichikawa T, Koarai A, Yamada M, Numakura T, Onodera K, Tanaka R, Sato K, Yanagisawa S, Okazaki T, Tamada T, Kikuchi T, Ichinose M. Possible role of Krüppel-like factor 5 in the remodeling of small airways and pulmonary vessels in chronic obstructive pulmonary disease. Respir Res. 2016 Jan 20;17:7. doi: 10.1186/s12931-016-0322-y. PMID: 26792671; PMCID: PMC4719583.
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  19. Wu Y, Chen S, Shao Y, Su Y, Li Q, Wu J, Zhu J, Wen H, Huang Y, Zheng Z, Chen X, Ju X, Huang S, Wu X, Hu Z. KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer. Adv Sci (Weinh). 2023 Nov;10(31):e2304638. doi: 10.1002/advs.202304638. Epub 2023 Sep 13. PMID: 37702443; PMCID: PMC10625120.
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