Regulation of SOX10 stability via ubiquitination-mediated degradation by Fbxw7α modulates melanoma cell migration

Lv, Xiaobin; Wu, Wei; Tang, Xiaofeng; Wu, Yanqing; Zhu, Yingting; Liu, Yujie; Cui, Xiaona; Chu, Jianping; Hu, Pengnan; Li, Jingjing; Guo, Qiannan; Zhang, Cai; Wu, Juan; Hu, Kaishun; Ouyang, Nengyong

doi:10.18632/oncotarget.5639

Cited by 21 publications

(23 citation statements)

References 46 publications

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“…While future studies will be required to assess biological significance of these phosphorylation sites in vivo , a similar shift in protein stability for another SOXE family member, SOX9, has been implicated in lung cancer metastasis [ 78 ]. Additionally, phosphorylation at SOX10 T240 and T244 is consistent with previous data showing GSK3B-dependent SOX10 ubiquitination at this region by FBXW7 E3 ligase, as protein phosphorylation is required prior to addition of the ubiquitin moiety [ 79 ]. Our analysis supports and extends this data, identifying T240 phosphorylation in melanoma cells and demonstrating decreased protein stability of SOX10 T240A compared to WT protein, as assayed in MeWo melanoma cells.…”

Section: Discussionsupporting

confidence: 90%

Identification and functional analysis of SOX10 phosphorylation sites in melanoma

et al. 2018

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The transcription factor SOX10 plays an important role in vertebrate neural crest development, including the establishment and maintenance of the melanocyte lineage. SOX10 is also highly expressed in melanoma tumors, and SOX10 expression increases with tumor progression. The suppression of SOX10 in melanoma cells activates TGF-β signaling and can promote resistance to BRAF and MEK inhibitors. Since resistance to BRAF/MEK inhibitors is seen in the majority of melanoma patients, there is an immediate need to assess the underlying biology that mediates resistance and to identify new targets for combinatorial therapeutic approaches. Previously, we demonstrated that SOX10 protein is required for tumor initiation, maintenance and survival. Here, we present data that support phosphorylation as a mechanism employed by melanoma cells to tightly regulate SOX10 expression. Mass spectrometry identified eight phosphorylation sites contained within SOX10, three of which (S24, S45 and T240) were selected for further analysis based on their location within predicted MAPK/CDK binding motifs. SOX10 mutations were generated at these phosphorylation sites to assess their impact on SOX10 protein function in melanoma cells, including transcriptional activation on target promoters, subcellular localization, and stability. These data further our understanding of SOX10 protein regulation and provide critical information for identification of molecular pathways that modulate SOX10 protein levels in melanoma, with the ultimate goal of discovering novel targets for more effective combinatorial therapeutic approaches for melanoma patients.

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Section: Discussionsupporting

confidence: 90%

Identification and functional analysis of SOX10 phosphorylation sites in melanoma

et al. 2018

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“…The above procedures were performed as previously described 37 . The gels were run under the same experimental conditions and the original whole gel blots were included in the supplementary data .…”

Section: Methodsmentioning

confidence: 99%

LncRNA PANDAR regulates the G1/S transition of breast cancer cells by suppressing p16INK4A expression

Sang

Tang

et al. 2016

Sci Rep

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It has been reported that lncRNA PANDAR (promoter of CDKN1A antisense DNA damage-activated RNA) is induced as a result of DNA damage, and it regulates the reparation of DNA damage. In this study, we investigated the role of lncRNA PANDAR in the progression of breast cancer and found that PANDAR was up-regulated in breast cancer tissues and cell lines. The knockdown of PANDAR suppresses G1/S transition of breast cancer cells. We demonstrated mechanistically that the regulation of G1/S transition by PANDAR was partly due to the transcriptional modulation of p16INK4A. Moreover, we showed that PANDAR impacted p16INK4A expression by regulating the recruitment Bmi1 to p16INK4A promoter. To our knowledge, this is the first study which showed the functional roles and mechanisms of PANDAR in regulating the progression of breast cancer. The PANDAR/Bmi1/p16INK4A axis could serve as novel targets for breast cancer therapy.

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“…This procedure was detailed previously (23). Briefly, protein lysates were resolved through 10% SDS-PAGE and electrophoretically transferred to a PvDF (polyvinylidene difluoride) membrane (Millipore, USA).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR-129-2 by promoter hypermethylation regulates breast cancer cell proliferation and apoptosis

Tang

Liu

et al. 2016

Oncology Reports

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Abstract. Aberrant expression of the miR-129 family has been found in several types of cancer, yet its expression and potential biologic role in breast cancer remain largely unknown. In the present study, we found that miR-129-2 was consistently downregulated in the breast cancer specimens and cell lines. Overexpression of miR-129-2-3p markedly suppressed breast cancer cell proliferation and induced its apoptosis. In addition, a luciferase reporter assay revealed that miR-129-2-3p suppressed BCL2L2 expression. Furthermore, BCL2L2 was able to reverse miR-129-2-3p-mediated cell apoptosis, indicating that BCL2L2 plays a crucial role in mediating the tumor-suppressive role of miR-129-2-3p. Moreover, bisulfite DNA sequencing PCR (BSP) analysis identified that promoter hypermethylation was responsible for the downregulation of miR-129-2 in breast cancer. Collectively, our findings indicate that miR-129-2 is downregulated in breast cancer cells by promoter hypermethylation. Moreover, downregulation of miR-129-2 results in BCL2L2 overexpression and disease progression in breast cancer patients.

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Regulation of SOX10 stability via ubiquitination-mediated degradation by Fbxw7α modulates melanoma cell migration

Cited by 21 publications

References 46 publications

Identification and functional analysis of SOX10 phosphorylation sites in melanoma

Identification and functional analysis of SOX10 phosphorylation sites in melanoma

LncRNA PANDAR regulates the G1/S transition of breast cancer cells by suppressing p16INK4A expression

Downregulation of miR-129-2 by promoter hypermethylation regulates breast cancer cell proliferation and apoptosis

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