The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

Xu, Jie; Zhou, Weihua; Yang, Fei; Chen, Guoan; Li, Haomin; Zhao, Yongchao; Liu, Pengyuan; Li, Hua; Tan, Mingjia; Xiong, Xiufang; Sun, Yi

doi:10.1038/ncomms14002

Cited by 67 publications

(91 citation statements)

References 80 publications

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“…2A). We have recently defined the consensus-binding motif (TSXXXS) required for FBXW2 to bind to its substrates, such as SKP2 (22) and β-catenin (23). Examination of the MSX2 protein sequence indeed identified such a motif, which is evolutionarily conserved ( 43 SSLPFS 48 ) (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

Yin

Xie

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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SOX2 is a key transcription factor that plays critical roles in maintaining stem cell property and conferring drug resistance. However, the underlying mechanisms by which SOX2 level is precisely regulated remain elusive. Here we report that MLN4924, also known as pevonedistat, a small-molecule inhibitor of neddylation currently in phase II clinical trials, down-regulates SOX2 expression via causing accumulation of MSX2, a known transcription repressor of SOX2 expression. Mechanistic characterization revealed that MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds to MSX2 and promotes MSX2 ubiquitylation and degradation. Likewise, FBXW2 overexpression shortens the protein half-life of MSX2, whereas FBXW2 knockdown extends it. We further identified hypoxia as a stress condition that induces VRK2 kinase to facilitate MSX2–FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. Biologically, expression of FBXW2 or SOX2 promotes tumor sphere formation, which is blocked by MSX2 expression. By down-regulating SOX2 through inactivation of FBXW2 E3 ligase, MLN4924 sensitizes breast cancer cells to tamoxifen in both in vitro and in vivo cancer cell models. Thus, a negative cascade of the FBXW2–MSX2–SOX2 axis was established, which regulates stem cell property and drug resistance. Finally, an inverse correlation of expression was found between FBXW2 and MSX2 in lung and breast cancer tissues. Collectively, our study revealed an anticancer mechanism of MLN4924. By inactivating FBXW2, MLN4924 caused MSX2 accumulation to repress SOX2 expression, leading to suppression of stem cell property and sensitization of breast cancer cells to tamoxifen.

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Section: Resultsmentioning

confidence: 99%

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

Yin

Xie

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Both β-TrCP1 and β-TrCP2 are the substrate of CRL1 E3 ligase Several F-box proteins, including β-TrCP, are unstable and degraded by proteasomes [7][8][9][10]. However, how β-TrCP1/2 protein stability is regulated in vivo remains poorly understood.…”

Section: Resultsmentioning

confidence: 99%

The cross talk of two family members of β-TrCP in the regulation of cell autophagy and growth

et al. 2019

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β-transducin repeat-containing protein (β-TrCP), one of the best-characterized substrate recognition components of the SKP1-CUL1-F-box (SCF) E3 ligase, has two distinct paralogs, β-TrCP1 and β-TrCP2, expressed in mammals. Through governing the ubiquitination and degradation of numerous key regulators, β-TrCP1/2 regulates various cellular physiological and pathological processes. However, whether and how these two proteins cross talk and whether they regulate cell autophagy and proliferation in different manners is completely unknown. Herein, we report that β-TrCP1 and β-TrCP2 are the physiological substrates of SCF E3 ligase and target each other for degradation that is dependent on their β-TrCP degron sequences. Furthermore, glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1. Finally, we found that β-TrCP2, not β-TrCP1, preferentially degrades DEPTOR and REDD1, the inhibitors of mTORC1, to activate mTORC1, leading to autophagy inhibition and cell growth. Thus, our study demonstrates that β-TrCP1 and β-TrCP2 mutually target each other for degradation and that β-TrCP2 acts as a dominant paralog in the regulation of cell autophagy and growth, which might be a promising anticancer target.

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“…The functions of (SKP2 or CRLs) as both direct regulators of cyclin-dependent kinases (CDKs) and gene transcription regulators have been well-characterized [11,12]. SKP2 always acts as a classic oncogene by posttranscriptional regulation of oncosuppressors and functions via cell cycle related mechanisms in a variety of human cancers [13][14][15][16]. The previous HCC studies about SKP2 have paid more attention on CKS1/SKP2 as the cell cycle regulator or SKP2 negatively correlation to tumor suppressors that might be a diagnostic or therapeutic target [14,17,18].…”

Section: Introductionmentioning

confidence: 99%

SKP2 Promotes Hepatocellular Carcinoma Progression Through Nuclear AMPK-SKP2-CARM1 Signaling Transcriptionally Regulating Nutrient-Deprived Autophagy Induction

Wei

Yan

et al. 2018

Cell Physiol Biochem

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Background/Aims: SKP2 overexpression has been associated with poor prognosis in numerous cancers. The mechanisms of autophagy in the tumor pathogenesis have been a research focus recently. How the SKP2 involved in autophagy expresses oncogenic characteristics, especially in HCC, are largely unclear. Methods: The expression of SKP2 was detected by qPCR, Western blot, Immunohistochemical (IHC) and Immunofluorescence (IF) techniques. SKP2 was knocked down or overexpressed by lentivirus transfection in HCC cells. Functional assays such as CCK8 assays, transwell migration and invasion assays, and colony formation assays were performed to determine the role of SKP2 in HCC. Furthermore, autophagy was induced by glucose deprivation in HCC cells followed by monitoring of the levels and distributions of SKP2, CARM1 and AMPK. Results: Our data showed that SKP2 levels were significantly increased in HCC cell lines and HCC tissues rather than corresponding normal liver tissues, and augmented SKP2 levels were statistically correlated with tumor grade, size and metastases. By up-regulation or down-regulation of SKP2 in HCC cells, we confirmed that SKP2 encourages proliferation, migration, invasion, and colony formation. We then found that SKP2 was inhibited, CARM1 increased and AMPKα2 became activated in the nucleus under glucose deprivation induced autophagy. Moreover, we discovered that SKP2 was repressing CARM1 in the nucleus under nutrient-sufficient conditions in HCC. Conclusions: We show that SKP2 promotes HCC progression and its nuclear functions of autophagy induction with CARM1 and AMPK, which may provide a potential target for HCC therapy.

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The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

Cited by 67 publications

References 80 publications

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

The cross talk of two family members of β-TrCP in the regulation of cell autophagy and growth

SKP2 Promotes Hepatocellular Carcinoma Progression Through Nuclear AMPK-SKP2-CARM1 Signaling Transcriptionally Regulating Nutrient-Deprived Autophagy Induction

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