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

Abstract

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.

METTL14 decreases FTH1 mRNA stability via m6A methylation to promote sorafenib-induced ferroptosis of cervical cancer

“…Previous studies have demonstrated that the PI3K/Akt signaling pathway is commonly aberrantly activated in various tumors, such as hepatocellular carcinoma 21 and colorectal cancer. 22 Evidence indicated that inhibiting the PI3K/Akt pathway may sensitize cancer cells to ferroptosis induction, offering a promising strategy to prevent carcinogenic progression. 23 Therefore, for further exploration of the underlying signaling pathway, we investigated the effects of METTL14 and FTH1 on the PI3K/Akt pathway.…”

MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis

“…Interestingly, KLF2 has a suppressive function in many cancers, including PCa, implying that miR-15b-3p promotes PCa progression by inhibiting KLF2. We hypothesized that KLF2 must facilitate ferroptosis because recent studies on clear cell renal cell carcinoma and colorectal cancer have reported that KLF2 induces this form of cell death via the GPX4 and PI3K/AKT pathways 29 , 39 . Our findings strongly support this hypothesis.…”

Ferroptosis and its role in gastric and colorectal cancers

“…KLF2 belongs to the zinc finger family and low expression in CRC patient tissues and cell lines is associated with poor prognosis in CRC. Overexpression of KLF2 reduces GSH peroxidase 4 expression to induce ferroptosis and inhibits PI3K/AKT signaling pathway to suppress CRC cell invasion, migration and EMT [ 126 ]. Cytochrome P450 1B1 (CYP1B1), a heme sulfate monooxygenase, that is highly expressed in CRC tumor tissue.…”