Abstract
Polycomb group (PcG) proteins regulate transcription, playing a key role in stemness and differentiation. Deregulation of PcG members is known to be involved in cancer pathogenesis. Emerging evidence suggests that CBX2, a member of the PcG protein family, is overexpressed in several human tumors, correlating with lower overall survival. Unraveling the mechanisms regulating CBX2 expression may thus provide a promising new target for anticancer strategies. Here we show that the HDAC inhibitor SAHA regulates CBX2 stability via a SUMO-triggered ubiquitin-mediated pathway in leukemia. We identify CBX4 and RNF4 as the E3 SUMO and E3 ubiquitin ligase, respectively, and describe the specific molecular mechanism regulating CBX2 protein stability. Finally, we show that CBX2-depleted leukemic cells display impaired proliferation, underscoring its critical role in regulating leukemia cell tumorogenicity. Our results show that SAHA affects CBX2 stability, revealing a potential SAHA-mediated anti-leukemic activity though SUMO2/3 pathway.
Highlights
SUMOylation is a post-translational modification (PTM) that regulates target protein function, playing a critical role in cellular processes such as DNA damage response, cell cycle progression, apoptosis, and cellular stress response [1,2,3]
We identified the specific molecular pathway and key players regulating CBX2 stability, demonstrating that CBX4 and RNF4 act as the E3 Small ubiquitin-like modifier (SUMO) and E3 ubiquitin ligase, respectively
Western blot analysis revealed that SUMO2/ 3 silencing limits SAHA-mediated CBX2 degradation compared to shSCR negative control (Fig. 2c)
Summary
SUMOylation is a post-translational modification (PTM) that regulates target protein function, playing a critical role in cellular processes such as DNA damage response, cell cycle progression, apoptosis, and cellular stress response [1,2,3]. CBX proteins link the activity of PRC1 with PRC2, serving as critical regulators of PcG-mediating activity. While the functional role of some CBX proteins in cancer has been largely described [15,16,17], recent reports support. We describe a novel SAHA-mediated mechanism of CBX2 post-translational regulation. We found that CBX2 undergoes SAHA-induced SUMO2/3 modification and that. CBX2 SUMOylation promotes its ubiquitination and proteasome-dependent degradation. Our study provides the first evidence of a non-canonical SAHA-mediated antitumorigenic activity via CBX2 SUMOylation and degradation
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