Small ubiquitin-related modifier-1 modification regulates all-trans-retinoic acid-induced differentiation via stabilization of retinoic acid receptor α

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 alpha (RAR alpha), protecting it from degradation. Moreover, our results suggested that Lys399 is a major site for SUMO-1 conjugation of RAR alpha. We also found that RAR alpha enhanced the transcription of its target genes, which might also contribute to the enhanced differentiating effects of ATRA; however, mutation of Lys399 of RAR alpha inhibits the extents of both SUMO-1 modification and ATRA-induced differentiation. Together, these results indicate that SUMO-1 modification of RAR alpha is a potent mechanism for balancing proliferation and differentiation by controlling the stability of RAR alpha in cancer cells. SUMO-1 modification may thus serve an important role in controlling ATRA-induced cell differentiation in cancers.