*3.3.3 Is there potential molecular plasticity of KLF4 in cancer and wound healing?*

KLF4 is a transcription factor with multiple functions in different physiological and pathological conditions, notably in cancer development. For example, KLF4 is well known for its tumor suppressive effect on tumor development in the gastrointestinal tract [102]. However, high expression of KLF4 is associated with skin cancer and breast cancer development [56, 103, 104], suggesting a tumor promoting function of KLF4 in these tissues. Recently, a tumor suppressive function of KLF4 was also reported in breast cancer [105]. These contradictory reports suggest context-dependent functions of KLF4 in cancer development [106]. At a molecular level, different KLF4 transcripts were found in testis [107], and alternative splicing of KLF4 has been proposed to explain context-dependent functions of KLF4 [108]. Consistently, an oncogenic KLF4 isoform, named KLF4α, has been found in both pancreatic cancer [109] and breast cancer [110]. In line with these observations, there is dynamic expression of KLF4 isoforms in mouse embryogenesis [111]. Interestingly, another human KLF4 isoform with an additional 34 amino acidfragment in the C-terminal region has been reported in leukemia patients [112] and in myeloid cells [113], which further supports the importance of differential expression of KLF4 in different conditions.

We speculate that the existence of different isoforms of KLF4 and possibly relative ratios of these isoforms may explain different functions of KLF4 in cancer development and even in wound healing. Because KLF4 is a transcription factor that regulates gene expression, different isoforms of KLF4 will have different patterns of gene regulation of the downstream targets. In analogy to MDSC dynamics and plasticity, we propose a concept of KLF4 plasticity, which reflects the dynamic nature of KLF4 expression under different conditions. It is likely that under one condition, a major isoform of KLF4 regulates a group of genes that are responsible for one signaling transduction pathway. This pathway may be linked to one functional or phenotypical MDSC group. Under a different condition, another KLF4 isoform dominates and regulates a different group of genes and a different signaling pathway. This kind of differential regulation may cause the plastic change of MDSCs in cancer or wound healing. To confirm our hypothesis, future experiments will be needed to characterize the different KLF4 isoforms during the dynamic change of MDSCs. Validation of our hypothesis will not only reveal novel molecular mechanisms whereby KLF4 regulates MDSC plasticity, but also help design KLF4-based therapeutic strategies to manipulate MDSC plasticity in the treatment of cancer and wound healing.

### **4. Conclusion remarks**

Studies of immune cell plasticity have recently gained momentum due to their novel functions in tissue repair and robustness beside their well-known functions in system defense. MDSCs, as a myeloid population with unique functions in tumor and tissue repair, are less studied regarding their phenotypical and functional plasticity, compared to macrophages and neutrophils. Given the ample evidence showing MDSC plasticity in cancer and wound healing, it is essential to elucidate the underlying molecular mechanisms in order to harness MDSCs in tissue repair and cancer treatment. In the meantime, we have shown KLF4 as a key molecule to regulate MDSC plasticity in cancer, wound healing, and allergic asthma. KLF4-controlled FSP-1 expression and possible epigenetic alterations are two possible mechanisms underlying MDSC plasticity. In addition, the existence of different KLF4 isoforms prompts us to hypothesize that KLF4 isoforms control gene expression of different signaling pathways that may contribute to MDSC dynamics and plasticity in both cancer and wound healing. In this regard, future studies to characterize different KLF4 isoforms during MDSC plastic changes and the relevant signaling pathways will pave the way to harness MDSC plasticity in the treatment of cancer and wound healing.

#### **Acknowledgements**

This work was supported by NSF HRD-1436222 and SC INBRE grant (NIH P20GM103499). We also thank Ms. Anna Harper for her proofreading of the manuscript.

**119**

**Author details**

Medicine, Columbia, SC, USA

College, Columbia, SC, USA

, Samir Raychoudhury2

\*Address all correspondence to: walden.ai@benedict.edu

provided the original work is properly cited.

and Walden Ai2

1 Department of Cell Biology and Anatomy, University of South Carolina School of

2 Department of Biology, Chemistry and Environmental Health Science, Benedict

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*

Daping Fan1

*KLF4-Mediated Plasticity of Myeloid-Derived Suppressor Cells (MDSCs)*

*DOI: http://dx.doi.org/10.5772/intechopen.89151*

### **Conflict of interest**

The authors declare no conflict of interest.

*KLF4-Mediated Plasticity of Myeloid-Derived Suppressor Cells (MDSCs) DOI: http://dx.doi.org/10.5772/intechopen.89151*
