KLF4α stimulates breast cancer cell proliferation by acting as a KLF4 antagonist

Abstract

Krüppel-like factor 4 (KLF4), a transcription factor involved in both tumor suppression and oncogenesis in various human tumors, is subject to alternative splicing that produces KLF4α. KLF4α is primarily expressed in the cytoplasm because it lacks exon 3 of KLF4, which contains the nuclear localization signal. The role of KLF4 in breast cancer remains unclear and nothing is known yet about the expression and function of the isoform KLF4α. Here, we show that KLF4α is expressed in normal and tumoral tissue of the breast and provide evidence that the KLF4α/KLF4(full-length) (FL) ratio is increased in tumors compared to corresponding normal tissue. Forced increase of the KLF4α/KLF4(FL) ratio in the metastatic breast cancer cell line MDA-MB-231 decreases the levels of E-Cadherin, p21Cip1, and p27Kip1, three known KLF4(FL) target genes, and stimulates cell proliferation. We suggest that cytoplasmic KLF4α binds to KLF4(FL) and retains it in the cytoplasm thereby antagonizing the gene regulatory activities of KLF4(FL) in the nucleus. Our results establish KLF4α as a KLF4 isoform that opposes the function of KLF4(FL) and as an important factor in the complex and unresolved role of KLF4(FL) in breast carcinogenesis.

Keratinocytes Isolated From Individual Cleft Lip/Palate Patients Display Variations in Their Differentiation Potential in vitro

“…CaCl 2 was the most robust inducer of IRF6 , GRHL3 , and KLF4 in H7-Ep (CLP) and Cx-Ep (control) cells (Figure 7A and Supplementary Figure S4 ). We also tested the levels of KLF4α , which is a KLF4 isoform that was recently shown to antagonize the function of KLF4 and to stimulate cancer cell proliferation ( Ferralli et al, 2016 ). In contrast to KLF4 , KLF4α was not induced under differentiating conditions, and consequently, cell differentiation resulted in a reduced KLF4α / KLF4 ratio in both cell cultures (Figure 7A ).…”

“…KLF4α is one of the main isoforms of KLF4 and was found to be over-expressed in pancreatic cancer and to correlate with poor patient prognosis ( Wei et al, 2010 ). More recently, it was shown that KLF4α is able to antagonize the function of KLF4 in breast cancer and that an increased ratio of KLF4α/KLF4 induced cancer cell proliferation ( Ferralli et al, 2016 ). Here, we show for the first time that KLF4α as well as the ratio KLF4α/KLF4 drastically decrease under differentiating conditions in primary normal and CLP keratinocytes (Figure 7 ).…”

The Effects of Combinatorial Genistein and Sulforaphane in Breast Tumor Inhibition: Role in Epigenetic Regulation

“…KLF4 can activate and/or repress transcription depending on which transcription factors it interacts with and also on its target gene. Studies have indicated that p21 acts like a switch and modulates the activity of KLF4 [ 56 ]. Some studies have reported that KLF4 activates telomerase reverse transcriptase (TERT) expression and contributes to the maintenance of self-renewal in embryonic stem cells [ 57 , 58 ].…”

Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma

“…KLF4 has been extensively studied in the context of tumors, and current data suggest that it can act as either a tissue-specific tumor-inhibiting or a tumor-promoting gene, with the underlying mechanism remaining unclear 6. KLF4 has been reported to inhibit tumorigenesis and/or malignant properties in a variety of contexts, including neuroblastoma, leukaemia, and pancreatic, lung, and colon cancer 7.…”