title: Small ubiquitin-related modifier-1 modification regulates all-trans-retinoic acid-induced differentiation via stabilization of retinoic acid receptor α.
abstract: 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 (RARα), protecting it from degradation. Moreover, our results suggested that Lys399 is a major site for SUMO-1 conjugation of RARα. We also found that RARα enhanced the transcription of its target genes, which might also contribute to the enhanced differentiating effects of ATRA; however, mutation of Lys399 of RARα inhibits the extents of both SUMO-1 modification and ATRA-induced differentiation. Together, these results indicate that SUMO-1 modification of RARα is a potent mechanism for balancing proliferation and differentiation by controlling the stability of RARα in cancer cells. SUMO-1 modification may thus serve an important role in controlling ATRA-induced cell differentiation in cancers.
authors.affiliation: Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Zibo
authors.initials: Z
authors.lastname: Chen
authors.forename: Pingge
authors.initials: P
authors.lastname: Zhao
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Ma
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Meidan
authors.initials: M
authors.lastname: Ying
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D018922:HL-60 Cells; D006801:Humans; D055550:Protein Stability; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D025842:SUMO-1 Protein / Q000502:physiology*; D058207:Sumoylation; D014212:Tretinoin / Q000502:physiology*
chemical_list: C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D025842:SUMO-1 Protein; D014212:Tretinoin
keywords: SUMOylation; differentiation; retinoic acid; retinoic acid receptor α; small ubiquitin-related modifier-1