The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice

Zubin Zhang, Jiefei Tong, Xiaowen Tang, Jiaxiang Juan, Biyin Cao, Rose Hurren, Guodong Chen, Paul Taylor, Xin Xu, Chang Xin Shi, Juan Du, Jian Hou, Guanghui Wang, Depei Wu, Alexander Keith Stewart, Aaron D. Schimmer, Michael F. Moran, Xinliang Mao

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The transcription factor c-Maf is extensively involved in the pathophysiology of multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, affinity chromatography and mass spectrometry were used to identify c-Maf ubiquitination-associated proteins, from which the E3 ligase HERC4 was found to interact with c-Maf and catalyzed its polyubiquitination and subsequent proteasome-mediated degradation. HERC4 mediated polyubiquitination at K85 and K297 in c-Maf, and this polyubiquitination could be prevented by the isopeptidase USP5. Further analysis on the NCI-60 cell line collection revealed that RPMI 8226, a MM-derived cell line, expressed the lowest level of HERC4. Primary bone marrow analysis revealed HERC4 expression was high in normal bone marrow, but was steadily decreased during myelomagenesis. These findings suggested HERC4 played an important role in MM progression. Moreover, ectopic HERC4 expression decreased MM proliferation in vitro, and delayed xenograft tumor growth in vivo. Therefore, modulation of c-Maf ubiquitination by targeting HERC4 may represent a new therapeutic modality for MM.

Original languageEnglish (US)
Pages (from-to)1676-1686
Number of pages11
JournalBlood
Volume127
Issue number13
DOIs
StatePublished - Mar 31 2016

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Medicine(all)
  • Hematology
  • Cell Biology

Cite this

Zhang, Z., Tong, J., Tang, X., Juan, J., Cao, B., Hurren, R., Chen, G., Taylor, P., Xu, X., Shi, C. X., Du, J., Hou, J., Wang, G., Wu, D., Stewart, A. K., Schimmer, A. D., Moran, M. F., & Mao, X. (2016). The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice. Blood, 127(13), 1676-1686. https://doi.org/10.1182/blood-2015-07-658203