Proteolysis of methylated SOX2 protein is regulated by L3MBTL3 and CRL4DCAF5 ubiquitin ligase

Zhang, Chunxiao; Feng, Lu; Saxena, Lovely; Hoang, Nam V.; Yu, Jiekai; Alejo, Salvador; Lee, Logan; Qi, Dandan; Lu, Fei; Sun, Hong; Zhang, Hui

doi:10.1074/jbc.ra118.005336

Cited by 43 publications

(87 citation statements)

References 51 publications

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“…On the other hand, SOX2 is induced by TGFβ via SOX4 (32), or by SIRT1 via epigenetic modification (33). At the posttranslational level, SOX2 was reported to be ubiquitylated and destabilized by CUL4A DET1-COP1 E3 ligase (34) and by ubiquitin-conjugating enzyme UBE2S (35), whereas methylated SOX2 was ubiquitylated and destabilized by HECT domain-containing WWP2 E3 ligase (36) and by the L3MBTL3-CRL4 DCAF5 ubiquitin ligase complex (37).…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…94 Furthermore, SET7-mediated SOX2 methylation at K42 is preferably recognized by ubiquitin E3 ligase CRL4 DCAF5 for subsequent SOX2 ubiquitylation and degradation, which is another mechanism of controlling the self-renewal and pluripotency of ESCs. 105 On the other hand, protein demethylase LSD1 and the methyl-binding protein PHF20L1 are likely to prevent SET7-mediated SOX2 monomethylation to inhibit SOX2 ubiquitylation and degradation to maintain the self-renewal of ESCs. 95 Ubiquitin-conjugating enzyme E2S (UBE2S) decorates SOX2 through the formation of K11-linked polyubiquitin chains at K123 to facilitate SOX2 proteasomal degradation, thus regulating the self-renewal and pluripotent status of ESCs and repressing SOX2-mediated ESC differentiation toward the neural ectodermal lineage.…”

Section: Role In Regulation Of Key Signaling Pathwaysmentioning

confidence: 99%

Functional characterization of SOX2 as an anticancer target

Zhang

Xiong

Sun

2020

Sig Transduct Target Ther

138

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SOX2 is a well-characterized pluripotent factor that is essential for stem cell self-renewal, reprogramming, and homeostasis. The cellular levels of SOX2 are precisely regulated by a complicated network at the levels of transcription, post-transcription, and posttranslation. In many types of human cancer, SOX2 is dysregulated due to gene amplification and protein overexpression. SOX2 overexpression is associated with poor survival of cancer patients. Mechanistically, SOX2 promotes proliferation, survival, invasion/ metastasis, cancer stemness, and drug resistance. SOX2 is, therefore, an attractive anticancer target. However, little progress has been made in the efforts to discover SOX2 inhibitors, largely due to undruggable nature of SOX2 as a transcription factor. In this review, we first briefly introduced SOX2 as a transcription factor, its domain structure, normal physiological functions, and its involvement in human cancers. We next discussed its role in embryonic development and stem cell-renewal. We then mainly focused on three aspects of SOX2: (a) the regulatory mechanisms of SOX2, including how SOX2 level is regulated, and how SOX2 cross-talks with multiple signaling pathways to control growth and survival; (b) the role of SOX2 in tumorigenesis and drug resistance; and (c) current drug discovery efforts on targeting SOX2, and the future perspectives to discover specific SOX2 inhibitors for effective cancer therapy.

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“…It is well documented that the main pluripotency TFs NANOG, SOX2, KLF4, and OCT4 are tightly regulated by ubiquitination and deubiquitination in the pluripotent state and upon induced differentiation ( Figure 2). For instance, the regulation of OCT4 poly‐ubiquitination implicates several E3 Ub ligases . While F‐box/WD repeat‐containing protein 8 (FBXW8) and Itchy E3 ubiquitin protein ligase (ITCH) are mainly regulating the abundance of OCT4 in the pluripotent state; WW‐domain containing E3 ubiquitin protein ligase 2 (WWP2), Double PHD finger 2 (DPF2), Tripartite containing motif 32 (TRIM32) are regulating OCT4 stability at the onset of differentiation .…”

Section: Ubiquitination Regulates the Stability And Activity Of Transmentioning

confidence: 99%

Ubiquitin Dynamics in Stem Cell Biology: Current Challenges and Perspectives

Dieuleveult

Miotto

2020

BioEssays

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Ubiquitination plays a central role in the regulation of stem cell self‐renewal, propagation, and differentiation. In this review, the functions of ubiquitin dynamics in a myriad of cellular processes, acting along side the pluripotency network, to regulate embryonic stem cell identity are highlighted. The implication of deubiquitinases (DUBs) and E3 Ubiquitin (Ub) ligases in cellular functions beyond protein degradation is reported, including key functions in the regulation of mRNA stability, protein translation, and intra‐cellular trafficking; and how it affects cell metabolism, the micro‐environment, and chromatin organization is discussed. Finally, unsolved issues in the field are emphasized and will need to be tackled in order to fully understand the contribution of ubiquitin dynamics to stem cell self‐renewal and differentiation.

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Proteolysis of methylated SOX2 protein is regulated by L3MBTL3 and CRL4DCAF5 ubiquitin ligase

Cited by 43 publications

References 51 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

Functional characterization of SOX2 as an anticancer target

Ubiquitin Dynamics in Stem Cell Biology: Current Challenges and Perspectives

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