Krüppel-like Factor-9 and Krüppel-like Factor-13: Highly Related, Multi-Functional, Transcriptional Repressors and Activators of Oncogenesis

Abstract

Specificity Proteins/Krüppel-like Factors (SP/KLF family) are a conserved family of transcriptional regulators. These proteins share three highly conserved, contiguous zinc fingers in their carboxy-terminus, requisite for binding to cis elements in DNA. Each SP/KLF protein has unique primary sequence within its amino-terminal and carboxy-terminal regions, and it is these regions which interact with co-activators, co-repressors, and chromatin-modifying proteins to support the transcriptional activation and repression of target genes. Krüppel-like Factor 9 (KLF9) and Krüppel-like Factor 13 (KLF13) are two of the smallest members of the SP/KLF family, are paralogous, emerged early in metazoan evolution, and are highly conserved. Paradoxically, while most similar in primary sequence, KLF9 and KLF13 display many distinct roles in target cells. In this article, we summarize the work that has identified the roles of KLF9 (and to a lesser degree KLF13) in tumor suppression or promotion via unique effects on differentiation, pro- and anti-inflammatory pathways, oxidative stress, and tumor immune cell infiltration. We also highlight the great diversity of miRNAs, lncRNAs, and circular RNAs which provide mechanisms for the ubiquitous tumor-specific suppression of KLF9 mRNA and protein. Elucidation of KLF9 and KLF13 in cancer biology is likely to provide new inroads to the understanding of oncogenesis and its prevention and treatments.

Keywords: Krüppel-like factor 13 (KLF13); Krüppel-like factor 9 (KLF9); future directions; lncRNA; miR; oncogenesis; pathways.

Figure 1

Multiple sequence alignment of mammalian KLF9 (panel (A)) and KLF13 (panel (B)) proteins. Human KLF13 protein has two isoforms; isoform 1’s sequence is shown (the protein that is described in the literature). KLF13 isoform 2 has a carboxy-terminus distinct from that of KLF13 isoform 1 and contains only one zinc finger (https://www.ncbi.nlm.nih.gov/gene/51621, accessed on 3 August 2023). Sequence data were aligned using Multiple Sequence Comparison by Log-Expectation (MUSCLE) [6]. Colors: red—small (small + hydrophobic (incl aromatic—Y)); blue—acidic; magenta—basic—H; green—hydroxyl + sulfhydryl + amine + G residues.

Figure 2

Multiple sequence alignment of human KLF9 and KLF13 isoform 1 proteins. The boundaries of the three zinc fingers are indicated [61]. Sequence data were aligned using Multiple Sequence Comparison by Log-Expectation (MUSCLE) [6]. Colors: red—small (small + hydrophobic (incl aromatic—Y)); blue—acidic; magenta—basic—H; green—hydroxyl + sulfhydryl + amine + G residues.

Figure 3

Post-translational modifications (serine and threonine phosphorylation, lysine acetylation, lysine ubiquitylation) mapped on human KLF9 and human KLF13 proteins. Data are from PhosphoSitePlus (v6.7.1.1) (https://www.phosphosite.org/homeAction.action, accessed on 3 August 2023), representing a collation of data from multiple targeted and mass spectrometry-based proteomics studies. The y-axis shows the relative strength (i.e., experimental evidence) of the presence of a site modification (note: the data are not restricted to cancer states, but also include that for normal tissues and other pathophysiological states). Zf-C2H: demarcates each of the three zinc fingers.

Figure 4

Summary and comparison of tumor-suppressing and tumor-promoting properties of KLF9 and KLF13. Created with BioRender.com.

Figure 5

Cells expressing KLF9 and KLF13 transcripts in human colon tumors and associated normal colon tissue (Human Colon Cancer Atlas (scRNAseq) within the Single Cell Portal was queried) (https://singlecell.broadinstitute.org/single_cell, accessed on 16 May 2022) [232]. Data represent a global view of the sampled colon cells (t-distributed Stochastic Neighbor Embedding, tSNE). Key: B, B cells; Epi, epithelial cells; Mast, mast cells; Myeloid, myeloid cells; Plasma, plasma cells; Strom, all stromal cell types—fibroblasts, endothelial, pericytes, etc; TNKILC—T, NK, ILC cell types.