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Small ubiquitin‐related modifier‐1 modification regulates all‐ trans ‐retinoic acid‐induced differentiation via stabilization of retinoic acid receptor α
Author(s) -
Zhou Qian,
Zhang Lei,
Chen Zibo,
Zhao Pingge,
Ma Yaxi,
Yang Bo,
He Qiaojun,
Ying Meidan
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12840
Subject(s) - retinoic acid , sumo protein , cellular differentiation , retinoic acid receptor , microbiology and biotechnology , ubiquitin , retinoid , tretinoin , cancer cell , transcription factor , biology , chemistry , cancer research , biochemistry , cancer , gene , genetics
Small ubiquitin‐related modifier‐1 ( SUMO ‐1) modification has been implicated in many important cellular processes, including cell cycle progression, apoptosis, cellular proliferation, and development, but its role in all‐ trans ‐retinoic acid ( ATRA )‐induced differentiation processes of cancer cells remains unclear. Here, we report for the first time that ATRA ‐induced differentiation of leukemia and osteosarcoma is accompanied by a decrease in the level of SUMO ‐1 protein. Our results also demonstrated that depletion or inhibition of SUMO ‐1 blocks ATRA ‐induced differentiation, suggesting that SUMO ‐1 is critical for the differentiation effect of ATRA . Further studies indicated that SUMO ‐1‐promoted ATRA ‐induced differentiation might be associated with the stabilization of retinoic acid receptor α ( RAR α), protecting it from degradation. Moreover, our results suggested that Lys399 is a major site for SUMO ‐1 conjugation of RAR α. We also found that RAR α enhanced the transcription of its target genes, which might also contribute to the enhanced differentiating effects of ATRA ; however, mutation of Lys399 of RAR α inhibits the extents of both SUMO ‐1 modification and ATRA ‐induced differentiation. Together, these results indicate that SUMO ‐1 modification of RAR α is a potent mechanism for balancing proliferation and differentiation by controlling the stability of RAR α in cancer cells. SUMO ‐1 modification may thus serve an important role in controlling ATRA ‐induced cell differentiation in cancers. Structured digital abstractSUMO1 physically interacts with RAR-alpha by anti bait coip ( 1 , 2 , 3 ) SUMO-1 physically interacts with RAR-alpha by anti tag coimmunoprecipitation ( View interaction ) SUMO1 and RAR-alpha colocalize by fluorescence microscopy ( View interaction )