Two Sides of the Same Coin: The Roles of KLF6 in Physiology and Pathophysiology

Abstract

The Krüppel-like factors (KLFs) family of proteins control several key biological processes that include proliferation, differentiation, metabolism, apoptosis and inflammation. Dysregulation of KLF functions have been shown to disrupt cellular homeostasis and contribute to disease development. KLF6 is a relevant example; a range of functional and expression assays suggested that the dysregulation of KLF6 contributes to the onset of cancer, inflammation-associated diseases as well as cardiovascular diseases. KLF6 expression is either suppressed or elevated depending on the disease, and this is largely due to alternative splicing events producing KLF6 isoforms with specialised functions. Hence, the aim of this review is to discuss the known aspects of KLF6 biology that covers the gene and protein architecture, gene regulation, post-translational modifications and functions of KLF6 in health and diseases. We put special emphasis on the equivocal roles of its full-length and spliced variants. We also deliberate on the therapeutic strategies of KLF6 and its associated signalling pathways. Finally, we provide compelling basic and clinical questions to enhance the knowledge and research on elucidating the roles of KLF6 in physiological and pathophysiological processes.

Thecis-regulatory effects of modern human-specific variants

“…5d, Supplementary File 3 ). All of these TFs had a positive correlation between changes in their predicted binding affinity and changes in expression of their bound sequences, reflective of their known capability to promote transcription 55–63 . Of note, the use of a minimal promoter with basal activity in the MPRA design means that transcriptional repression is less likely to be detected, and therefore, further investigation is required in order to identify potential repressive activity in these sequences (see Discussion).…”

The cis-regulatory effects of modern human-specific variants

“…We found that changes to the motifs of 14 TFs were predictive of expression changes ( Figure 3—figure supplement 2d , Supplementary file 3b ). All of these TFs had a positive correlation between changes in their predicted binding affinity and changes in expression of their bound sequences, reflective of their known capability to promote transcription ( Suske, 2017 ; Frey-Jakobs et al, 2018 ; Bruderer et al, 2013 ; Frietze et al, 2010 ; Song et al, 2003 ; Zhu et al, 2018 ; Ji et al, 2020 ; Morita et al, 2016 ; Syafruddin et al, 2020 ). Of note, the use of an mP with basal activity in the MPRA design means that transcriptional repression is less likely to be detected, and therefore, further investigation is required in order to identify potential repressive activity in these sequences (see Discussion).…”

Exploring the Significance of the Exon 4-Skipping Isoform of the ZNF217 Oncogene in Breast Cancer

“…This was thoroughly validated by RNAseq or RT-qPCR analyses in primary breast tumors from independent cohorts. Alternative splicing of other members of the Krüppellike factor (KLF) gene family, including the KLF6 tumor suppressor and the KLF4 regulator of stem cell pluripotency, has been previously described and shown to result in the production of several isoforms with specific biological functions and biomarker value (22)(23)(24)(25). Our study thus highlights ZNF217 as a further member of the KLF family that is susceptible to splicing modulation in a tumorigenic context, generating distinct isoforms.…”