Downregulation of FHL1 protein in glioma inhibits tumor growth through PI3K/AKT signaling

Abstract

Human four-and-a-half LIM domains protein 1 (FHL1) is a member of the FHL protein family, which serves an important role in multiple cellular events by interacting with transcription factors using its cysteine-rich zinc finger motifs. A previous study indicated that FHL1 was downregulated in several types of human cancer and served a role as a tumor suppressive gene. The overexpression of FHL1 inhibited tumor cell proliferation. However, to the best of our knowledge, there is no evidence to confirm whether FHL1 affected glioma growth, and the molecular mechanisms through which FHL1 represses tumor development remain unclear. In the present study, the expression level of FHL1 was determined using immunohistochemical staining in 114 tumor specimens from patients with glioma. The results indicated that FHL1 expression was negatively associated with the pathological grade of gliomas. Furthermore, Kaplan-Meier survival curves demonstrated that the patients with an increased FHL1 expression exhibited a significantly longer survival time, suggesting that FHL1 may be a prognostic marker for glioma. The protein level of FHL1 was relatively increased in the U251 glioma cell line compared with that in the U87 cell line. Therefore, FHL1 was knocked down in U251 by siRNA and overexpressed in U87, and it was identified that FHL1 significantly decreased the activation of PI3K/AKT signaling by interacting with AKT. Further experiments verified that FHL1 inhibited the growth of gliomas in vivo by modulating PI3K/AKT signaling. In conclusion, the results of the present study demonstrated that FHL1 suppressed glioma development through PI3K/AKT signaling.

FHL1 promotes glioblastoma aggressiveness through regulating EGFR expression

“…When we prepared our manuscript, a new report showed that downregulation of FHL1 inhibits glioma cell growth in a PI3K/AKT pathway‐dependent manner [27]. These results are not in line with our findings.…”

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing

“…FHL1 interacts with transcription factors and signaling proteins, thus modulating gene transcription and signaling pathways (29, 33). FHL1 suppresses tumor growth through several mechanisms, including interaction with tumor-regulating estrogen receptors and SMAD family proteins, and reduction of PI3K/AKT signaling (29,34,35). The FHL1 3’-UTR was significantly lengthened (P=0.029), and FHL1 gene expression was significantly enriched, in CPSF3 knockdown cells, as compared with shNTC controls (Fig.…”

“…Intriguingly, this list included multiple downregulated oncogenes, including SMAD Family Member 6 (SMAD6) and Mitogen-Activated Protein Kinase Kinase 6 We next sought to determine if any of the APA-regulated oncogenes or tumor suppressors were directly responsible for CPSF3 knockdown-mediated attenuation of cell proliferation. We focused on FHL1, as it has been reported to possess tumor suppressor activity in non-PDAC cancers (29)(30)(31)(32), but has no known roles in PDAC biology. FHL1 interacts with transcription factors and signaling proteins, thus modulating gene transcription and signaling pathways (29,33).…”

FHL3 Contributes to EMT and Chemotherapy Resistance Through Up-Regulation of Slug and Activation of TGFβ/Smad-Independent Pathways in Gastric Cancer

“…For TGFb/ Smad-independent way, PI3K/Akt, MAPK, Nuclear Factor Kappa-B (NF-kB), Hedgehog, and Wnt/b-catenin pathways were upstream regulators of EMT-TFs (38)(39)(40)(41). Some studies pointed out that FHLs can increase the activation and transcription of Akt to promote tumor growth and progression in glioma, breast cancer, and ovarian cancer (30,42,43). Other published papers showed that FHLs interfere with the MAPK/ERK pathway, resulting in radiotherapy resistance in pancreatic cancer (44).…”