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.

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.

Breast cancer has the highest incidence among cancers and is the most frequent cause of death in women worldwide. The detailed mechanism of the pathogenesis of breast cancer has not been fully elucidated, and there remains a lack of effective treatment methods for the disease. SUMOylation covalently conjugates a large amount of cellular proteins, and affects their cellular localization and biological activity to participate in numerous cellular processes. SUMOylation is an important process and imbalance of SUMOylation results in the progression of human diseases. Increasing evidence shows that numerous SUMOylated proteins are involved in the occurrence and development of breast cancer. This review summarizes a series of studies on protein SUMOylation in breast cancer in recent years. The study of SUMOylated proteins provides a comprehensive understanding of the pathophysiology of breast cancer and provides evolving therapeutic strategies for the treatment of breast cancer.

Edited by George DeMartinoSentrin/small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2)-deficient mice develop spontaneous seizures in early life because of a marked reduction in M currents, which regulate neuronal membrane excitability. We have previously shown that hyper-SUMOylation of the Kv7.2 and Kv7.3 channels is critically involved in the regulation of the M currents conducted by these potassium voltage-gated channels. Here, we show that hyper-SUMOylation of the Kv7.2 and Kv7.3 proteins reduced binding to the lipid secondary messenger PIP 2 . CaM1 has been shown to be tethered to the Kv7 subunits via hydrophobic motifs in its C termini and implicated in the channel assembly. Mutation of the SUMOylation sites on Kv7.2 and Kv7.3 specifically resulted in decreased binding to CaM1 and enhanced CaM1-mediated assembly of Kv7.2 and Kv7.3, whereas hyper-SUMOylation of Kv7.2 and Kv7.3 inhibited channel assembly. SENP2-deficient mice exhibited increased acetylcholine levels in the brain and the heart tissue because of increases in the vagal tone induced by recurrent seizures. The SENP2-deficient mice develop seizures followed by a period of sinus pauses or atrioventricular conduction blocks. Chronic administration of the parasympathetic blocker atropine or unilateral vagotomy significantly prolonged the life of the SENP2-deficient mice. Furthermore, we showed that retigabine, an M-current opener, reduced the transcription of SUMO-activating enzyme SAE1 and inhibited SUMOylation of the Kv7.2 and Kv7.3 channels, and also prolonged the life of SENP2-deficient mice. Taken together, the previously demonstrated roles of PIP2, CaM1, and retigabine on the regulation of Kv7.2 and Kv7.3 channel function can be explained by their roles in regulating SUMOylation of this critical potassium channel.

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