KLF14 alleviated breast cancer invasion and M2 macrophages polarization through modulating SOCS3/RhoA/Rock/STAT3 signaling

Chu, Jian; Hu, Xingchi; Li, Changchun; Li, Tangya; Fan, Huiwen; Jiang, Guoqin

doi:10.1016/j.cellsig.2022.110242

Cited by 27 publications

(26 citation statements)

References 28 publications

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“…The hypermethylation of KLF14 could result in the dysregulation of the cell cycle and DNA repair ability by influencing the TRIM59 methylation status in patients with AD 26,49 . Furthermore, the hypermethylation level of KLF14 was correlated to its downregulation in breast cancer cells 50 .…”

Section: Discussionmentioning

confidence: 94%

“…Luo et al and Boot et al also showed that the overexpression of KLF14 could promote cell proliferation and cell cycle and decrease cell apoptosis in LNCaP cells and thyroid cancer cells 51,52 . However, several studies reported that KLF14 overexpression inhibited cell growth and proliferation in breast cancer 50 , colorectal cancer 53 , and KRAS oncogenic mutant cancer cells 54 . This discrepancy remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of KLF14 accelerated cellular senescence and aging

Hou¹,

Qiao²,

Wang

et al. 2023

Preprint

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Aging has been considered as a risk factor in many diseases, thus, comprehensively understanding the cellular and molecular mechanisms of delayed aging is important. Here we investigated whether KLF14 is a suppressor of cellular senescence and aging. In our research, KLF14 levels significantly decreased not only in the serum and lymphocytes of healthy people but also in the cells and tissues of mice with aging. We performed in vitro and in vivo experiments on cells and mice to reveal the function of KLF14 in aging. KLF14 deficiency facilitates cellular senescence and aging-related pathologies in C57BL/6 mice, whereas KLF14 overexpression attenuates cellular senescence. Mechanistically, KLF14 delays aging by binding to the POLD1 promoter to positively regulate POLD1 expression. Remarkably, cellular senescence mediated by KLF14 downregulation could be alleviated by POLD1expression. In addition, perhexiline, an agonist of KLF14, could delay cellular senescence and aging-related pathologies in SAMP8 mice by inducing POLD1 expression, as perhexiline could enhance the effect of KLF14’s transcription activation to POLD1 by elevating the binding level of KLF14 to the POLD1 promoter. Our data indicate that KLF14 might be a critical element in aging by upregulating POLD1 expression, indicating that the activation of KLF14 may delay aging and aging-associated diseases.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Downregulation of KLF14 accelerated cellular senescence and aging

Hou¹,

Qiao²,

Wang

et al. 2023

Preprint

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“… 18 In breast cancer, it has been demonstrated that the polarisation of M2 macrophage was modulated by KLF14 via SOCS3/RhoA/ROCK signalling pathway, thereby suppressing tumour growth. 71 In addition, inhibition of RhoA/ROCK signalling pathway suppresses macrophage polarisation. 72 Our study illustrated that the ROCK inhibitor WXWH0265 inhibited M2 macrophage polarisation to reduce PF.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that ROCK inhibitors could reduce the number of macrophages in the PF immune microenvironment 18 . In breast cancer, it has been demonstrated that the polarisation of M2 macrophage was modulated by KLF14 via SOCS3/RhoA/ROCK signalling pathway, thereby suppressing tumour growth 71 . In addition, inhibition of RhoA/ROCK signalling pathway suppresses macrophage polarisation 72 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarisation through phosphorylation of STAT3

Cheng

Zhang

et al. 2022

Clinical & Translational Med

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Background Emerging evidence provides mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), and rare anti‐PF therapeutic method has promising effect in its treatment. Rho‐associated coiled‐coil kinases (ROCK) inhibition significantly ameliorates bleomycin‐induced PF and decreases macrophage infiltration, but the mechanism remains unclear. We established bleomycin and radiation‐induced PF to identify the activity of WXWH0265, a newly designed unselective ROCK inhibitor in regulating macrophages. Methods Bleomycin‐induced PF was induced by intratracheal instillation and radiation‐induced PF was induced by bilateral thoracic irradiation. Histopathological techniques (haematoxylin and eosin, Masson's trichrome and immunohistochemistry) and hydroxyproline were used to evaluate PF severity. Western blot, quantitative real‐time reverse transcription‐polymerase chain reaction and flow cytometry were performed to explore the underlying mechanisms. Bone marrow‐derived macrophages (BMDMs) were used to verify their therapeutic effect. Clodronate liposomes were applied to deplete macrophages and to identify the therapeutic effect of WXWH0265. Results Therapeutic administration of ROCK inhibitor ameliorates bleomycin‐induced PF by inhibiting M2 macrophages polarisation. ROCK inhibitor showed no significant anti‐fibrotic effect in macrophages‐depleted mice. Treatment with WXWH0265 demonstrated superior protection effect in bleomycin‐induced PF compared with positive drugs. In radiation‐induced PF, ROCK inhibitor effectively ameliorated PF. Fibroblasts co‐cultured with supernatant from various M2 macrophages phenotypes revealed that M2 macrophages stimulated by interleukin‐4 promoted extracellular matrix production. Polarisation of M2 macrophages was inhibited by ROCK inhibitor treatment in vitro. The p‐signal transducer and activator of transcription 3 (STAT3) in lung tissue and BMDMs was significantly decreased in PF in vivo and vitro after treated with ROCK inhibitors. Conclusion Inhibiting ROCK could significantly attenuate bleomycin‐ and radiation‐induced PF by regulating the macrophages polarisation via phosphorylation of STAT3. WXWH0265 is a kind of efficient unselective ROCK inhibitor in ameliorating PF. Furthermore, the results provide empirical evidence that ROCK inhibitor, WXWH0265 is a potential drug to prevent the development of PF.

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“…By contrast, in BC, KLF14 reduced M2 macrophage polarization and related promoting factors of the tumor microenvironment (TGF-β, MMP9, and VEGF). Mechanistically, this is achieved by activating the transcription of suppressor of cytokine signaling-3, then blocking the activation of RhoA/Rock/Signal transducer and activator of transcription-3 (STAT3) signaling ( 186 ). STAT3 is a tumor promoter that helps tumor cells evade natural killer cell-mediated immune surveillance ( 187 ), and KLF5 is also associated with it.…”

Section: Implications Of Klfs In Tumor Developmentmentioning

confidence: 99%

Krüppel-like factors in tumors: Key regulators and therapeutic avenues

Zhang

Yao

et al. 2023

Front. Oncol.

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Krüppel-like factors (KLFs) are a group of DNA-binding transcriptional regulators with multiple essential functions in various cellular processes, including proliferation, migration, inflammation, and angiogenesis. The aberrant expression of KLFs is often found in tumor tissues and is essential for tumor development. At the molecular level, KLFs regulate multiple signaling pathways and mediate crosstalk among them. Some KLFs may also be molecular switches for specific biological signals, driving their transition from tumor suppressors to promoters. At the histological level, the abnormal expression of KLFs is closely associated with tumor cell stemness, proliferation, apoptosis, and alterations in the tumor microenvironment. Notably, the role of each KLF in tumors varies according to tumor type and different stages of tumor development rather than being invariant. In this review, we focus on the advances in the molecular biology of KLFs, particularly the regulations of several classical signaling pathways by these factors, and the critical role of KLFs in tumor development. We also highlight their strong potential as molecular targets in tumor therapy and suggest potential directions for clinical translational research.

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KLF14 alleviated breast cancer invasion and M2 macrophages polarization through modulating SOCS3/RhoA/Rock/STAT3 signaling

Cited by 27 publications

References 28 publications

Downregulation of KLF14 accelerated cellular senescence and aging

Downregulation of KLF14 accelerated cellular senescence and aging

Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarisation through phosphorylation of STAT3

Krüppel-like factors in tumors: Key regulators and therapeutic avenues

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