KMT5C (Lysine Methyltransferase 5C)

Furthermore, the higher KMT5C level is associated with better survival, while a lower KMT5C level is associated with perineural invasion in HNSC patients. KMT5C levels regulate targets involved in cell proliferation and represent a potential biomarker for predicting survival and perineural invasion in HNSC.

Together with high levels of centromere transcription and corresponding R-loop formation, RB-deficient cells exhibit centromere DNA breaks and local activation of ATR that correspond with increased centromere localization of Aurora B, destabilization of kinetochore-microtubule attachments, and an increase in anaphase defects. Importantly, reduction of DNA damage, ATR activity, and mitotic defects following inhibition of RNA Pol II, or targeted repression of centromere transcription through centromere tethering of Suv420h2, support that mitotic defects in RB-deficient cells are linked to centromere transcription.

Consistently, immunofluorescence analysis of pyruvate carboxylase (PC), keratin 17 (KRT17), and KMT5C substantiated distinct expression patterns in tumor boundary and center lesions. This study initially presents the spatial proteomic heterogeneity landscape in RB with ONI and uncovers its molecular reprogramming.

In this review, we explore the dysregulation of KMT5C-mediated H4K20me3 in cancer, providing a comprehensive overview of its known functions. We also highlight recent findings that suggest a novel, non-canonical pathway for H4K20me3 deposition by KMT5C, and, while early on, insight into future opportunities for therapeutic intervention.

Here, we demonstrated that inhibiting histone H4-lysine 20 (H4K20) methyltransferases SUV4-20H1 and SUV4-20H2 induced synthetic lethality in combination with the TOP2 poison etoposide in prostate cancer...Furthermore, SUV4-20H depletion and the subsequent changes in H4K20 methylation impaired the repair of TOP2-induced DNA breaks by disrupting BRCA1-mediated homologous recombination processes, ultimately leading to extensive cancer cell death and significant inhibition of prostate tumor growth in vivo. Overall, these findings demonstrate that targeting the epigenetic activity of SUV4-20H is a powerful strategy to enhance the efficacy of TOP2 poisons and may represent a therapeutic alternative in prostate cancer, where SUV4-20H2 expression emerges as a potential marker of aggressive disease and high metastatic risk.

Clinically, high expression levels of KMT5C in patients with NSCLC are associated with a lower response rate and worse clinical outcomes to ICB therapy. Therefore, these findings identify a previously unknown functional link between KMT5C and tumor immune evasion, and demonstrate that targeting KMT5C may be a potential therapeutic approach for enhancing the efficacy of NSCLC patients to ICB therapy.

Alterations induced by KMT5C knockdown were partly reversed by UPP1 inhibition. Overall, we demonstrate that KMT5C, recruited by NR2C2, suppresses OSCC progression by inhibiting UPP1 transcription in a H4K20me3-dependent way.

Finally, the expression of the signature genes was verified in ccRCC cells, and the effect of SGO1 on the malignant biological behavior of ccRCC cells was also verified by in vitro experiments. In conclusion, this LLPS prognostic signature may be a potential clinical prognostic and immunotherapeutic response-related indicator for ccRCC patients.

Importantly, the signature not only identified specific NEPC subtypes, such as large-cell neuroendocrine carcinoma, which is associated with very poor outcomes, but also predicted a poor prognosis for PCa cases that exhibit this molecular signature, even when they were not histopathologically classified as NEPC. This dual prognostic and classifier capability makes the 7-gene signature a robust tool for personalized medicine, providing a valuable resource for predicting disease progression and guiding treatment strategies in PCa management.

Understanding the molecular mechanisms that underlie SUV4-20H2-mediated effects on chromatin structure and gene expression may provide valuable insights into novel therapeutic strategies for targeting epigenetic alterations in cancer. Herein, we discuss structural and functional aspects of SUV4-20H2 in cancer onset, progression and prognosis, along with current targeting options.

Further developments are discussed that could bring us closer to a mechanistic understanding of catalysis of this important class of enzymes in the near future. The results described here illustrate the power of the investigation of enzyme mechanisms by the combined application of biochemical experiments and simulation technologies.

Additionally, KMT5C promoted the proliferation and EMT of ccRCC cells by controlling crucial EMT transcriptional factors. Together, these data suggested that KMT5C may act as an oncoprotein, guide molecular diagnosis, and shed light on novel drug development and therapeutic strategies for patients with ccRCC.