KMT5A (Lysine Methyltransferase 5A)

Importantly, 3 effectively inhibited tumor growth in vivo in two xenograft mouse models of SETD8-overexpressing MM cell lines. Collectively, our results establish 3 as a valuable chemical tool for exploring the biological functions of SETD8 and pave the way for further development of novel epigenetic therapies for MM.

Instead, we observed site-specific changes driven by altered expression of methyltransferases and demethylases, particularly decreased KMT1F (H3K9 methylation) and KMT2B (H3K4 methylation) and increased KDM2A (H3K36 demethylation), KDM3A (H3K9 demethylation), and KMT5A/SETD8 (H4K20 monomethylation). These findings reveal that the histone methylation landscape under hypoxia is governed by a compensatory interplay between one-carbon metabolism and chromatin-modifying enzyme regulation.

This method has also revealed changes in SET8-regulated substrate network among breast cancer missense mutations, collectively revealing insight into differential enzyme function in disease. By disentangling the substrate features that dictate PTM-inducing enzyme specificity, this approach demonstrates potential in uncovering enzyme-substrate networks within PTM pathways.

Findings from GC cells, organoids and PDX models demonstrated that overexpression of the miR-99b cluster sensitized GC to cisplatin, likely through its inhibitory effects on mitochondrial respiratory function, particularly OXPHOS...Moreover, elevated KMT5A expression and decreased miR-125a-5p expression indicated both poorer prognosis and chemo-resistance in patients with GC. This study highlights the multifaceted roles of the miR-99b cluster in GC and offers novel perspectives for the development of innovative therapeutics aimed at overcoming chemoresistance and enhancing treatment efficacy for GC patients.

SET8 facilitates radiation-induced migration in LUAD through the PTTG1-PI3K-AKT pathway, and SET8-associated genes may act as valuable markers for predicting radiotherapeutic efficacy in LUAD patients.

Finally, KMT5a also methylates lysine residues on nonhistone proteins, and KMT5a-induced methylation of key oncogenic and tumor suppressor proteins, including TP53, strongly affects cancer cell functions. Overall, KMT5a is overexpressed in a high percentage and wide variety of human cancers and has protumorigenic activity, which makes it a target for innovative therapy.

Our findings establish KMT5A as an epigenetic regulator that impairs CD8+T cell function. These findings demonstrate that genetic or pharmacological (eg, UNC0379) targeting of KMT5A in CD8+T cells represents a viable therapeutic strategy to augment effector functions and improve adoptive T-cell therapies, particularly CAR-T cells, for solid tumors.

Mechanistically, SETD8 promoted the expression of the mitochondrial outer membrane protein RHOT1 by increasing chromatin accessibility at the enhancer region, thereby reprogramming mitochondrial homeostasis. These findings improve our understanding of gene regulation through chromatin accessibility remodeling and establish a link between histone lysine methylation and mitochondrial homeostasis, suggesting a potential strategy for eliminating LSCs in t(8;21) AML.

Importantly, CDT2 depletion induces DNA aneuploidy and senescence via stabilization of histone lysine methyltransferase SET8, a CRL4CDT2 substrate, acting as a tumor suppressor. Collectively, the TRIM22-CDT2-SET8 axis is the key mediator of the p53/Rb signals in regulation of growth and survival of HPV-positive cervical carcinoma cells, Thus, CDT2 could serve as a prognostic biomarker and therapeutic target for these carcinomas.

In conclusion, OXCT1 interference reverses the KMT5A-induced enhancement of TNBC cell viability, proliferation, and PD-L1 expression. KMT5A promotes OXCT1 expression through histone methylation, and OXCT1 increases PGK1 protein stability through succinylation modification, thereby promoting aerobic glycolysis and immune escape in TNBC.

Our findings reveal a chromatin-based mechanism by which cells integrate metabolic status with transcriptional regulation to adapt to amino acid limitation. Loss of H4K20me1 and increased MYC activity act in parallel to prime the translational machinery during AA deprivation, enabling rapid recovery of protein synthesis upon nutrient restoration. This mechanism may help explain how cells maintain competitive growth potential under fluctuating nutrient conditions and has implications for understanding MYC-driven cancer progression.