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Article

KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors

1
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
2
Department of Medicine, Duke University, Durham, NC 27708, USA
3
Department of Biotechnology, Indian Institute of Technology, Kharagpur 721302, India
4
Duke Cancer Institute, Duke University, Durham, NC 27708, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Heiko Hermeking
Cancers 2021, 13(20), 5135; https://doi.org/10.3390/cancers13205135
Received: 27 August 2021 / Revised: 6 October 2021 / Accepted: 8 October 2021 / Published: 13 October 2021
Cancer is expected to be the leading cause of death due to noncommunicable diseases in the 21st century. Cancer-related mortality is largely due to metastasis. Cancer cells undergoing metastasis exhibit Epithelial–Mesenchymal Plasticity where they can transition from an epithelial to mesenchymal (EMT) or from a mesenchymal to epithelial (MET) phenotype. These transitions are crucial for the success of various stages of metastasis. Both these processes are modulated by multiple EMT-inducing and MET-inducing factors acting in concert. While EMT inducers are well-recognized, MET inducers are relatively poorly investigated. Here, we investigated the role of KLF4 through mechanism-based mathematical models and transcriptomic data analysis and identified it to be a potential MET inducer by suppressing one or more EMT inducers directly and/or indirectly.
Epithelial–Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)—TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2—are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2 and GRHL1/2). Here, using mechanism-based mathematical modeling, we show that transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote a phenotypic shift toward a more epithelial state, an observation suggested by the negative correlation of KLF4 with EMT-TFs and with transcriptomic-based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating the EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at the epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with the patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival. View Full-Text
Keywords: KLF4; Mesenchymal–Epithelial Transition (MET); Epithelial–Mesenchymal Plasticity (EMP); epigenetics; mathematical modeling KLF4; Mesenchymal–Epithelial Transition (MET); Epithelial–Mesenchymal Plasticity (EMP); epigenetics; mathematical modeling
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MDPI and ACS Style

Subbalakshmi, A.R.; Sahoo, S.; McMullen, I.; Saxena, A.N.; Venugopal, S.K.; Somarelli, J.A.; Jolly, M.K. KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors. Cancers 2021, 13, 5135. https://doi.org/10.3390/cancers13205135

AMA Style

Subbalakshmi AR, Sahoo S, McMullen I, Saxena AN, Venugopal SK, Somarelli JA, Jolly MK. KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors. Cancers. 2021; 13(20):5135. https://doi.org/10.3390/cancers13205135

Chicago/Turabian Style

Subbalakshmi, Ayalur R., Sarthak Sahoo, Isabelle McMullen, Aaditya N. Saxena, Sudhanva K. Venugopal, Jason A. Somarelli, and Mohit K. Jolly 2021. "KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors" Cancers 13, no. 20: 5135. https://doi.org/10.3390/cancers13205135

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