The Distinct Roles of Transcriptional Factor KLF11 in Normal Cell Growth Regulation and Cancer as a Mediator of TGF-β Signaling Pathway

Lin, Lili; Mahner, Sven; Jeschke, Udo; Hester, Anna

doi:10.3390/ijms21082928

Cited by 21 publications

(14 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…KLF11 is a TGF-β inducible immediate early gene (TIEG) and promotes the effects of TGF-β on cell growth by influencing the TGF-β-SMAD signaling pathway and regulating transcription of genes that induce either cell cycle arrest or apoptosis [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

et al. 2022

View full text Add to dashboard Cite

Progression of virtually all forms of chronic kidney disease (CKD) is associated with activation of pro-inflammatory and pro-fibrotic signaling pathways. Despite extensive research, progress in identifying therapeutic targets to arrest or slow progression of CKD has been limited by incomplete understanding of basic mechanisms underlying renal inflammation and fibrosis in CKD. Recent studies have identified Kruppel-like transcription factors that have been shown to play critical roles in renal development, homeostasis, and response to injury. Although KLF11 deficiency has been shown to increase collagen production in vitro and tissue fibrosis in other organs, no previous study has linked KLF11 to the development of CKD. We sought to test the hypothesis that KLF11 deficiency promotes CKD through upregulation of pro-inflammatory and pro-fibrogenic signaling pathways in murine unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis. We found that KLF11-deficiency exacerbates renal injury in the UUO model through activation of the TGF-β/SMAD signaling pathway and through activation of several pro-inflammatory chemokine signaling pathways. Based on these considerations, we conclude that agents increase KLF11 expression may provide novel therapeutic targets to slow the progression of CKD.

show abstract

Section: Discussionmentioning

confidence: 99%

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Disruption of TGFβ/Smad signaling is common in human cancers and facilitates tumor cells to evade TGFβ-induced cell inhibition (63, 64). Interestingly, KLF11 does suppress growth in untransformed cells and even transforms normal broblasts (39). However, it appears to be a pro-tumor regulator of several cancer types, e.g., pancreatic cancer, ovarian cancer, esophageal cancer, etc.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, KLF11 suppresses cell proliferation and induces cell apoptosis of untransformed cells such as pancreatic epithelial cells, normal ovary cells, etc., in vitro and in vivo (29,31,(36)(37)(38)(39). However, the role of KLF11 in carcinogenesis is context-dependent.…”

mentioning

confidence: 99%

“…Interestingly, KLF11 reveres its role as a cell growth suppressor in normal cells to a cell growth promoter in tumor cells of several cancer types, e.g., pancreatic cancer, ovarian cancer, etc. (39), suggesting that KLF11 might also be a cell growth-promoting factor in breast tumor cells. The incidental results of two studies reported that the genomic region of KLF11 is hypermethylated in lower-grade BC (40), and the mRNA expression of KLF11 is reduced in BC samples (36).…”

mentioning

confidence: 99%

“…Afterward, we explored the mechanism underlying KLF11-mediated BC progression from the tumor cell's perspective. It has been demonstrated that the role of KLF11 in other types of cancer cells is mainly related to cell growth, like cell proliferation or cell apoptosis (39). Furthermore, the functional signi cance of KLFs in BC tumor cells is distinct due to the different molecular subtypes of BC cell lines (16).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Transcriptional Factor KLF11 is a new prognostic biomarker and potential therapeutic target in human sporadic invasive breast cancer

Lin

Jeschke

Hester

et al. 2022

64. Kongress Der Deutschen Gesellschaft Für Gynäkologie Und Geburtshilfe E. V.

View full text Add to dashboard Cite

BackgroundBreast cancer (BC) is a heterogeneous disease characterized by distinct molecular subtypes. Krüppel like Factor (KLF) family members in BC have been widely studied. However, the roles of KLFs as tumorpromoters or tumor-suppressors are context-dependent. KLF11, as a member of this family, the expression pattern and prognostic relevance of which in BC remains unclear. MethodsTo clarify whether KLF11 acts as a tumor-promoter or a tumor-suppressor in BC, we explored the prognostic role of the KLF11 in BC patients by performing immunohistochemistry (IHC) staining of KLF11 in 298 patients samples. Then we correlated the expression to clinicopathological characteristics and survival outcomes. To investigate the function of KLF11 in tumor cells, we performed different assays of cell viability, cell proliferation, and cell apoptosis assays in three distinct molecular subtypes of BC cell lines with siRNA-mediated loss-of-function of KLF11. ResultsIn the BC patient cohort, We demonstrated that KLF11 was higher in highly proliferative BC and lowest in luminal A-like BC. Furthermore, "KLF11-high" BC patients had shorter disease-free survival (DFS), distantmetastasis-free survival (DMFS), and local recurrence-free survival (LRFS). High KLF11 expression remained an independent indicator for DFS and DMFS of BC. The multivariate cox regression-dependent, KLF11-related nomograms of DFS and DMFS showed high accuracy in predicting BC patients' 3-,5-and 10 -year survival probability. Our results indicate that KLF11 might play a pro-tumor role in BC.From the KLF11-BC tumor cells perspective, the cellular functional assays con rmed that KLF11 acts as a pro-tumor transcription factor (TF) in BC cells via promoting proliferation and/or decreasing cell apoptosis. However, due to neoplastic intratumor heterogeneity, different cancer molecular subtypes could have different underlying mechanisms. ConclusionsPrior research has demonstrated that KLF11 expression is lower in BC compared to healthy breast tissue.However, we now could show that high KLF11 expression in BC is probably pro-tumorigenic and is associated with an impaired prognosis. Our study indicates that KLF11, as a transcriptional factor, acts as a new prognostic biomarker and might also be potentially a synergistic or an alternative therapeutic target for conventional targeting treatments of human BC. BackgroundBreast cancer (BC) is a malignancy with high mortality among women (1-4). It is a complicated and heterogeneous disease characterized by diverse molecular subtypes. For clinical purposes, BC subtypes are classi ed according to the prognostic biomarkers: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the proliferation marker . The cutoff values for high versus low Ki-67 expression vary from 10-29% and remain debatable, thus limiting its clinical utility (6). In recent decades, speci c therapies based on these molecular subtypes-associated parameters, like endocrine therapies for ER-positive or anti-HER2 the...

show abstract

KLF2 inhibits colorectal cancer progression and metastasis by inducing ferroptosis via the PI3K/AKT signaling pathway

Jiang

Chen

et al. 2023

The Journal of Pathology CR

View full text Add to dashboard Cite

Krüppel‐like factor 2 (KLF2) belongs to the zinc finger family and is thought to be a tumor suppressor gene due to its low expression in various cancer types. However, its functional role and molecular pathway involvement in colorectal cancer (CRC) are not well defined. Herein, we investigated the potential mechanism of KLF2 in CRC cell invasion, migration, and epithelial–mesenchymal transition (EMT). We utilized the TCGA and GEPIA databases to analyze the expression of KLF2 in CRC patients and its correlation with different CRC stages and CRC prognosis. RT‐PCR, western blot, and immunohistochemistry assays were used to measure KLF2 expression. Gain‐of‐function assays were performed to evaluate the role of KLF2 in CRC progression. Moreover, mechanistic experiments were conducted to investigate the molecular mechanism and involved signaling pathways regulated by KLF2. Additionally, we also conducted a xenograft tumor assay to evaluate the role of KLF2 in tumorigenesis. KLF2 expression was low in CRC patient tissues and cell lines, and low expression of KLF2 was associated with poor CRC prognosis. Remarkably, overexpressing KLF2 significantly inhibited the invasion, migration, and EMT capabilities of CRC cells, and tumor growth in xenografts. Mechanistically, KLF2 overexpression induced ferroptosis in CRC cells by regulating glutathione peroxidase 4 expression. Moreover, this KLF2‐dependent ferroptosis in CRC cells was mediated by inhibiting the PI3K/AKT signaling pathway that resulted in the suppression of invasion, migration, and EMT of CRC cells. We report for the first time that KLF2 acts as a tumor suppressor in CRC by inducing ferroptosis via inhibiting the PI3K/AKT signaling pathway, thus providing a new direction for CRC prognosis assessment and targeted therapy.

show abstract

The Distinct Roles of Transcriptional Factor KLF11 in Normal Cell Growth Regulation and Cancer as a Mediator of TGF-β Signaling Pathway

Cited by 21 publications

References 85 publications

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

Transcriptional Factor KLF11 is a new prognostic biomarker and potential therapeutic target in human sporadic invasive breast cancer

KLF2 inhibits colorectal cancer progression and metastasis by inducing ferroptosis via the PI3K/AKT signaling pathway

Contact Info

Product

Resources

About