KMT5A (Lysine Methyltransferase 5A)

SETD8 promotes EMT and GC progression primarily by upregulating MCM7 expression, likely via an H4K20me1-dependent epigenetic mechanism. MCM7 acts as a key downstream effector. The SETD8/MCM7 axis represents a novel driver and potential therapeutic target in GC.

Mechanistically, loss of SETD8 phosphorylation in tumors results in a loss of H4K20 monomethylation (H4K20me1) deposition at oncogenic cholesterol biosynthesis and fetal intestinal genes, allowing for their activation in part through gain of YAP accessibility. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN-independent oncogenic consequence of APC loss.

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.