UBE2M (Ubiquitin Conjugating Enzyme E2 M)

Regarding clinical application, we identified micafungin as an inhibitor of UBE2M capable of suppressing the regulatory axis and, consequently, hindering CRC progression. Therefore, this study underscores the potential role of UBE2M in bridging neddylation with the cell cycle and holds promise for advancing targeted therapies in CRC treatment.

NLRP3 neddylation hinders its interaction with Trim31 and thereby inhibits its K48-linked ubiquitination and subsequent degradation. MLN4924, a potent compound NAE inhibitor in phase 1/2/3 clinical trials for cancers, alleviates psychological stress-induced NLRP3 inflammasome activation, microglia inflammatory activation, and anxiety-like behavior, suggesting novel clinical activity of MLN4924.

This study establishes UBE2M as a critical tumor suppressor in melanoma through the MKK7 neddylation-JNK-EGR1 axis and highlights its potential as a therapeutic target.

Consequently, global neddylation inhibitor MLN4924 (Pevonedistat) and UBE2F-CRL5 axis inhibitor HA-9104 were shown to downregulate neddylation, suppressing UBE2F activity and selectively inhibiting growth of Sdhb -deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability in this cell culture model of SDH-deficient PPGL.

Here we present data demonstrating that the combined inhibition of both processes using the compounds Rohinitib and MLN4924/Pevonedistat synergistically enhances the individual effects of each through the induction of apoptosis...Additionally, a cooperative regulation of BCL2 and TP53 expression was observed. These preclinical observations support future studies for their therapeutical application in CLL.

Ubiquitin-like modification genes are associated with poor prognosis due to their low methylation and high expression in cancers. Their genetic alterations impact cancer pathways, underscoring their potential as therapeutic targets and prognostic biomarkers.

Importantly, DCN1 inhibition attenuated UUO and UIRI-induced mouse renal fibrosis. Further studies revealed that DCN1 loss selectively inhibited cullin3 neddylation and induced its substrate NRF2 accumulation, thereby inhibiting TGFβ-Smad2/3 signaling pathway. Overall, blockade of neddylation through targeted inhibition of DCN1 contributes to alleviating renal fibrosis in vitro and in vivo, which may constitute a novel therapeutic strategy for renal fibrosis.

Additionally, Western blotting results confirmed that UBE2M deletion inhibited the activation of the NF-κB, ERK, and JAK-STAT signaling pathways. In conclusion, our findings indicate that specific deletion of UBE2M in macrophages protects against E. coli-induced sepsis by downregulating the excessive inflammatory response, potentially providing a novel strategy against sepsis by targeting UBE2M.

Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML. Together, we uncover the function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.

P2, N=36, Active, not recruiting, National Cancer Institute (NCI) | N=52 --> 36 | Trial completion date: Dec 2024 --> Oct 2025 | Trial primary completion date: Dec 2024 --> Nov 2023

P2, N=52, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Dec 2024 | Trial primary completion date: Oct 2024 --> Dec 2024

Functionally, silencing of UBE2M suppressed the growth of breast cancer cells by inducing cell cycle arrest and apoptosis and improved their sensitivity to fulvestrant both in vitro and in vivo. Altogether, our findings reveal that the UBE2M-ERα feedback loop drives breast cancer progression and fulvestrant resistance, suggesting UBE2M as a viable target for endocrine therapy of ER+ breast cancer.