Src-mediated phosphorylation converts FHL1 from tumor suppressor to tumor promoter

Wang, Xiang; Wei, Xiaofan; Yang, Yuan; Sun, Qing; Zhan, Jun; Zhang, Jing; Tang, Yan; Feng, Li; Ding, Lei; Ye, Qinong; Zhang, Hongquan

doi:10.1083/jcb.201708064

Cited by 27 publications

(26 citation statements)

References 48 publications

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“…Cells were transfected with pCMV-FLAG-FHL1 or pCMV-FLAG using Lipofectamine ® LTX &Plus Reagent (Thermo Fisher Scientific, Inc.). Co-IP was performed as previously described (17), with an anti-FLAG monoclonal antibody (Merck KGaA; cat. no.…”

Section: Co-immunoprecipitation (Ip)mentioning

confidence: 99%

“…FHL1 overexpression suppresses cell growth through cyclin D1 and E and p27 in head and neck squamous cell carcinoma (16). FHL1 may also be converted from a tumor suppressor to a cell growth accelerator, when FHL1 is phosphorylated by cytosolic tyrosine kinase Src (17). However, its exact role and molecular mechanism in gliomas is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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

Zhao

et al. 2020

Oncol Lett

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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.

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Section: Co-immunoprecipitation (Ip)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhao

et al. 2020

Oncol Lett

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“…When oncoprotein Src is overactivated, Src competitively binds with kindlin‐2 to FHL1 and mediates FHL1 phosphorylation. Phosphorylated FHL1 will release the inhibition of wild‐type FHL1 on tumor cells to promote cell proliferation and tumor growth [19]. In addition, knockdown of FHL1 in hepatic carcinoma cells (HCC) significantly increases the sensitivity of HCC cells to paclitaxel, but not to oxaliplatin by enhancing the paclitaxel‐induced activation of caspase‐3 and caspase‐9 [20].…”

mentioning

confidence: 99%

FHL1 promotes glioblastoma aggressiveness through regulating EGFR expression

et al. 2020

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The four-and-a-half LIM domain protein 1 (FHL1) plays a key role in multiple cancers. Here, we characterized its role in glioblastoma (GBM), the most common and incurable form of brain cancer. Overexpression of FHL1 promotes growth, migration, and invasion of GBM cells in vivo and in vitro. In contrast, FHL1 silencing by RNAi exhibits the opposite effects. FHL1 interacts with the transcription factor SP1 to upregulate epidermal growth factor receptor (EGFR) expression and activate the downstream signaling cascades, including Src, Akt, Erk1/2, and Stat3, leading to GBM malignancy. FHL1 is highly expressed and positively correlated with EGFR levels in human GBM, particularly those of the classical subtype. Our results suggest that the FHL1-SP1-EGFR axis plays a tumor-promoting role, and highlight the translational potential of inhibiting FHL1 for GBM treatment.

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“…FHL1 itself localizes to both focal adhesions and the cell nucleus, and acts as a tumor suppressor by inhibiting cell growth and migration. However, in this issue, reveal that FHL1 can also promote tumor growth when it is phosphorylated by the tyrosine kinase Src (1). …”

mentioning

confidence: 99%

“…Zhang and colleagues, led by Xiang Wang and Xiaofan Wei, focused on protein kinases that mediate integrin-based signaling at focal adhesions and found that the tyrosine kinase Src can bind to FHL1 and phosphorylate the protein on two tyrosine residues, Y149 and Y272 (1). …”

mentioning

confidence: 99%