Post-translational modification by SUMO (small ubiquitin-like modifier) proteins has been shown to regulate a variety of functions of proteins, including protein stability, chromatin organization, transcription, DNA repair, subcellular localization, proteinprotein interactions, and protein homeostasis. SENP (sentrin/SUMO-specific protease) regulates precursor processing and deconjugation of SUMO to control cellular mechanisms. SENP3, which is one of the SENP family members, deconjugates target proteins to alter protein modification. The effect of modification via SUMO and SENP3 is crucial to maintain the balance of SUMOylation and guarantee normal protein function and cellular activities. SENP3 acts as an oxidative stress-responsive molecule under physiological conditions. Under pathological conditions, if the SUMOylation process of proteins is affected by variations in SENP3 levels, it will cause a cellular reaction and ultimately lead to abnormal cellular activities and the occurrence and development of human diseases, including cardiovascular diseases, neurological diseases, and various cancers. In this review, we summarized the most recent advances concerning the critical roles of SENP3 in normal physiological and pathological conditions as well as the potential clinical implications in various diseases. Targeting SENP3 alone or in combination with current therapies might provide powerful targeted therapeutic strategies for the treatment of these diseases.

Neurological diseases are relatively complex diseases of a large system; however, the detailed mechanism of their pathogenesis has not been completely elucidated, and effective treatment methods are still lacking for some of the diseases. The SUMO (small ubiquitin‐like modifier) modification is a dynamic and reversible process that is catalyzed by SUMO‐specific E1, E2, and E3 ligases and reversed by a family of SENPs (SUMO/Sentrin‐specific proteases). SUMOylation covalently conjugates numerous cellular proteins, and affects their cellular localization and biological activity in numerous cellular processes. A wide range of neuronal proteins have been identified as SUMO substrates, and the disruption of SUMOylation results in defects in synaptic plasticity, neuronal excitability, and neuronal stress responses. SUMOylation disorders cause many neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. By modulating the ion channel subunit, SUMOylation imbalance is responsible for the development of various channelopathies. The regulation of protein SUMOylation in neurons may provide a new strategy for the development of targeted therapeutic drugs for neurodegenerative diseases and channelopathies.

Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, we showed that SOX9 is overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCL) harboring IGH-BCL2 translocations. SOX9 positivity in DLBCL correlates with advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole transcriptome analysis and CHIP-seq assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In DLBCL cell line xenograft models, SOX9 knockdown resulted in lower DHCR24 level, reduced cholesterol content and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell line with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrates that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCL.

Leukemia is a malignant disease of hematopoietic tissue characterized by the differentiation arrest and malignant proliferation of immature hematopoietic precursor cells in bone marrow. ERG (ETS-related gene) is an important member of the E26 transformation-specific (ETS) transcription factor family that plays a crucial role in physiological and pathological processes. However, the role of ERG and its modification in leukemia remains underexplored. In the present study, we stably knocked down or overexpressed ERG in leukemia cells and observed that ERG significantly promotes the proliferation and inhibits the differentiation of AML (acute myeloid leukemia) cells. Further experiments showed that ERG was primarily modified by SUMO2, which was deconjugated by SENP2. PML promotes the SUMOylation of ERG, enhancing its stability. Arsenic trioxide decreased the expression level of ERG, further promoting cell differentiation. Furthermore, the mutation of SUMO sites in ERG inhibited its ability to promote the proliferation and inhibit the differentiation of leukemia cells. Our results demonstrated the crucial role of ERG SUMOylation in the development of AML, providing powerful targeted therapeutic strategies for the clinical treatment of AML.