ADAMDEC1 and FGF2/FGFR1 signaling constitute a positive feedback loop to maintain GBM cancer stem cells

AbstractThe leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) is considered to be a stem cell marker in many normal tissues and promotes tissue development, regeneration, and repair. LGR6 is also related to the initiation and progression of some malignant tumors. However, the role of LGR6 in cervical cancer has not been reported. Here, immunohistochemistry and western blotting showed that LGR6 was significantly upregulated in cervical cancer, compared with the normal cervix. By analyzing The Cancer Genome Atlas database, LGR6 was found to be correlated with a poor prognosis of cervical cancer. Then, a small population of LGR6high cells isolated by using the fluorescence-activated cell sorting exhibited enhanced properties of cancer stem cells including self-renewal, differentiation, and tumorigenicity. Moreover, RNA sequencing revealed that LGR6 was correlated with the Wnt signaling pathway and TOP/FOP, reverse transcription-PCR, and western blotting further proved that LGR6 could activate the Wnt/β-catenin signaling pathway. Interestingly, LGR6 upregulated the expression of TCF7L2 by activating the Wnt/β-catenin pathway. Then, TCF7L2 combining with β-catenin in the nucleus enhanced LGR6 transcription by binding the promoter of LGR6, which further activated the Wnt signaling to form a positive feedback loop. Thus, our study demonstrated that LGR6 activated a novel β-catenin/TCF7L2/LGR6-positive feedback loop in LGR6high cervical cancer stem cells (CSCs), which provided a new therapeutic strategy for targeting cervical CSCs to improve the prognosis of cervical cancer patients.

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Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop

10.21203/rs.3.rs-56902/v1 ◽

2020 ◽

Author(s):

In-Gyu Kim ◽

Jei-Ha Lee ◽

Seo-Yeon Kim ◽

Chang-Kyu Heo ◽

Rae-Kwon Kim ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Transcriptional Activation ◽

Positive Feedback ◽

Feedback Loop ◽

Nuclear Translocation ◽

Positive Feedback Loop ◽

Targeting Therapy ◽

Mesenchymal Transition

Abstract Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches are limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) as a CSC-associated factor that promotes stemness and epithelial-to-mesenchymal transition in therapy-resistant non-small cell lung cancer (NSCLC) cells. Aberrantly activated PI3K/AKT pathway in therapy-resistant NSCLC cells promotes TSPYL5 phosphorylation at threonine-120 (pT120), which inhibits ubiquitination and stabilizes TSPYL5. TSPYL5 pT120 also supports SUMOylation, which leads to its nuclear translocation and functions as a transcriptional repressor of PTEN. Nuclear TSPYL5 also activates the transcription of CSC-associated genes, ALDH1 and CD44. Collectively, TSPYL5 pT120 maintains persistent CSC-like characteristics via transcriptional activation of CSC-associated genes and via a positive-feedback loop between the AKT/TSPYL5/PTEN and PTEN/PI3K/AKT signaling pathways. However, inhibition of TSPYL5 pT120 can block aberrant AKT/TSPYL5/PTEN cyclic signaling and cancer stemness. Our study suggests TSPYL5 as a novel target for cancer therapy.

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Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop

Communications Biology ◽

10.1038/s42003-021-02303-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

In-Gyu Kim ◽

Jei-Ha Lee ◽

Seo-Yeon Kim ◽

Chang-Kyu Heo ◽

Rae-Kwon Kim ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Transcriptional Activation ◽

Positive Feedback ◽

Feedback Loop ◽

Nuclear Translocation ◽

Negative Regulator ◽

Positive Feedback Loop ◽

Targeting Therapy

AbstractCancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches are limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) as an upstream regulator of CSC-associated genes in non-small cell lung cancer cells, and suggest as a therapeutic target for CSC elimination. TSPYL5 elevation is driven by AKT-dependent TSPYL5 phosphorylation at threonine-120 and stabilization via inhibiting its ubiquitination. TSPYL5-pT120 also induces nuclear translocation and functions as a transcriptional activator of CSC-associated genes, ALDH1 and CD44. Also, nuclear TSPYL5 suppresses the transcription of PTEN, a negative regulator of PI3K signaling. TSPYL5-pT120 maintains persistent CSC-like characteristics via transcriptional activation of CSC-associated genes and a positive feedback loop consisting of AKT/TSPYL5/PTEN signaling pathway. Accordingly, elimination of TSPYL5 by inhibiting TSPYL5-pT120 can block aberrant AKT/TSPYL5/PTEN cyclic signaling and TSPYL5-mediated cancer stemness regulation. Our study suggests TSPYL5 be an effective target for therapy-resistant cancer.

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