Table 1.
Summary of the molecular mechanisms responsible for the involvement of KLF4 in the most common cancer types. Since KLF4 is a transcription factor, almost all of its downstream targets are regulated at the level of transcriptional initiation. Thus we only include statements “positive” and “negative” to indicate whether the transcription of this particular target gene is regulated positively or negatively by KLF4.
| Cancer Type | Upstream Regulator/Downstream Target | Gene/Pathway | Molecular Mechanism | Reference |
|---|---|---|---|---|
| Colorectal cancer | upstream regulators | BMI1 | methylation of KLF4 promoter | [25] |
| miR-7-5p, miR-10b, miR-25-3p, miR-103/107, miR-130a, miR-135b, miR-153-1, miR-543 | negative regulation by microRNA | [12,13,14,15,16,17,22] | ||
| downstream targets | GINS4 | negative | [5] | |
| NDRG2 | positive | [4] | ||
| tumor microenvironment | myeloid cell infiltration | [9] | ||
| Breast cancer | upstream regulators | AR, DYRK2 | transcription of KLF4 | [42] |
| NFI-C | transcription of KLF4 | [31] | ||
| DDX3X | splicing of KLF4 primary transcript | [30] | ||
| miR-7, miR-1233-3p | negative regulation by microRNA | [29,40,41] | ||
| ATXN3 | KLF4 protein degradation | [36] | ||
| FBXO32 | KLF4 protein degradation | [37] | ||
| downstream targets | E-cadherin | positive | [32] | |
| LASS2 | positive | [33] | ||
| PFKP | positive | [39] | ||
| S100A14 | positive | [38] | ||
| Hepatocellular carcinoma | upstream regulators | EGFR | transcription of KLF4 | [64] |
| SET8 | transcription of KLF4 | [46] | ||
| SF3B4 | splicing of KLF4 primary transcript | [57] | ||
| miR-9-5p, miR-10b, miR-18a, miR-124 | negative regulation by microRNA | [52,53,54,55] | ||
| TRAF7 | KLF4 protein degradation | [51] | ||
| DDX17 | transcriptional transactivation activity of KLF4 | [56] | ||
| downstream targets | CD9, CD81 | positive | [62] | |
| EGFR | positive | [64] | ||
| EpCAM, CD133/Prominin-1 | positive | [66] | ||
| KLF11 | negative | [55] | ||
| MGLL | positive | [58,59] | ||
| miR-31 | positive | [61] | ||
| P-cadherin | positive | [63] | ||
| RYBP | positive | [60] | ||
| SIRT4 | positive | [46] | ||
| Smad7 | positive | [47] | ||
| Lung cancer | upstream regulators | SUR1, p70S6K, DNMT1 | methylation of KLF4 promoter | [78] |
| SIRT6, Snail | transcription of KLF4 | [76] | ||
| miR-25, miR-103, miR-145, miR-3120-5p | negative regulation by microRNA | [69,73,74,75] | ||
| MALAT1, TRHDE-AS1 | positive regulation by lncRNA | [74,75] | ||
| USP10 | KLF4 protein degradation | [71] | ||
| downstream targets | β-catenin | negative | [79] | |
| β-catenin, c-Met | inhibition of binding between c-Met and β-catenin | [79] | ||
| MMP2, PLAC8 | negative | [70,77] | ||
| TIMP3 | positive | [71] | ||
| Gastric cancer | upstream regulators | CagA, TET1 | methylation of KLF4 promoter | [92] |
| LINC00673, EZH2, DNMT1 | methylation of KLF4 promoter | [86] | ||
| miR-32, miR-103, miR-135b-5p, miR-155 | negative regulation by microRNA | [81,82,83,84,85] | ||
| SNHG5 | positive regulation by lncRNA | [82] | ||
| downstream targets | iASPP | negative | [88] | |
| PODXL | negative | [89] | ||
| STK33 | negative | [87] | ||
| Prostate cancer | upstream regulators | KMT2D | methylation of KLF4 promoter | [103] |
| LINC00673, DNMT1, DNMT3a, DNMT3b | methylation of KLF4 promoter | [96] | ||
| AR | transcription of KLF4 | [97] | ||
| miR-7, miR-32-5p, miR-148-3p, miR-152-3p | negative regulation by microRNA | [94,95,102] | ||
| downstream targets | AR | positive | [97] | |
| BIK | positive | [102] | ||
| IGF2 | positive | [104] | ||
| miR-1 | positive | [97] | ||
| miR-7 | positive | [94] | ||
| tumor microenvironment | pro-inflammatory states | [105] |