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UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling.

Publication ,  Journal Article
Dikshit, A; Jin, YJ; Degan, S; Hwang, J; Foster, MW; Li, C-Y; Zhang, JY
Published in: Cancer Res
November 15, 2018

UBE2N is a K63-specific ubiquitin conjugase linked to various immune disorders and cancer. Here, we demonstrate that UBE2N and its partners UBE2V1 and UBE2V2 are highly expressed in malignant melanoma. Silencing of UBE2N and its partners significantly decreased melanoma cell proliferation and subcutaneous tumor growth. This was accompanied by increased expression of E-cadherin, p16, and MC1R and decreased expression of melanoma malignancy markers including SOX10, Nestin, and ABCB5. Mass spectrometry-based phosphoproteomic analysis revealed that UBE2N loss resulted in distinct alterations to the signaling landscape: MEK/ERK signaling was impaired, FRA1 and SOX10 gene regulators were downregulated, and p53 and p16 tumor suppressors were upregulated. Similar to inhibition of UBE2N and MEK, silencing FRA1 decreased SOX10 expression and cell proliferation. Conversely, exogenous expression of active FRA1 increased pMEK and SOX10 expression, and restored anchorage-independent cell growth of cells with UBE2N loss. Systemic delivery of NSC697923, a small-molecule inhibitor of UBE2N, significantly decreased melanoma xenograft growth. These data indicate that UBE2N is a novel regulator of the MEK/FRA1/SOX10 signaling cascade and is indispensable for malignant melanoma growth. Our findings establish the basis for targeting UBE2N as a potential treatment strategy for melanoma.Significance: These findings identify ubiquitin conjugase UBE2N and its variant partners as novel regulators of MAPK signaling and potential therapeutic targets in melanoma. Cancer Res; 78(22); 6462-72. ©2018 AACR.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 15, 2018

Volume

78

Issue

22

Start / End Page

6462 / 6472

Location

United States

Related Subject Headings

  • Ubiquitin-Conjugating Enzymes
  • Tumor Microenvironment
  • Skin Neoplasms
  • Signal Transduction
  • SOXE Transcription Factors
  • Proto-Oncogene Proteins c-fos
  • Proteomics
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice, SCID
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Dikshit, A., Jin, Y. J., Degan, S., Hwang, J., Foster, M. W., Li, C.-Y., & Zhang, J. Y. (2018). UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling. Cancer Res, 78(22), 6462–6472. https://doi.org/10.1158/0008-5472.CAN-18-1040
Dikshit, Anushka, Yingai J. Jin, Simone Degan, Jihwan Hwang, Matthew W. Foster, Chuan-Yuan Li, and Jennifer Y. Zhang. “UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling.Cancer Res 78, no. 22 (November 15, 2018): 6462–72. https://doi.org/10.1158/0008-5472.CAN-18-1040.
Dikshit A, Jin YJ, Degan S, Hwang J, Foster MW, Li C-Y, et al. UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling. Cancer Res. 2018 Nov 15;78(22):6462–72.
Dikshit, Anushka, et al. “UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling.Cancer Res, vol. 78, no. 22, Nov. 2018, pp. 6462–72. Pubmed, doi:10.1158/0008-5472.CAN-18-1040.
Dikshit A, Jin YJ, Degan S, Hwang J, Foster MW, Li C-Y, Zhang JY. UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling. Cancer Res. 2018 Nov 15;78(22):6462–6472.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 15, 2018

Volume

78

Issue

22

Start / End Page

6462 / 6472

Location

United States

Related Subject Headings

  • Ubiquitin-Conjugating Enzymes
  • Tumor Microenvironment
  • Skin Neoplasms
  • Signal Transduction
  • SOXE Transcription Factors
  • Proto-Oncogene Proteins c-fos
  • Proteomics
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice, SCID