Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR...

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Epigenetic modifiers are increasingly recognized as key drivers in prostate cancer (PCa) development.
• The specific role of the histone methyltransferase KMT2D in PCa, particularly in Chinese populations, remains largely undefined.
• Understanding KMT2D's mutations, downstream pathways, and targets is crucial for PCa research.

Purpose of the Study:

• To investigate the mutational status and prognostic significance of KMT2D in Chinese prostate cancer patients.
• To elucidate the functional role of KMT2D in PCa cell proliferation, migration, and invasion.
• To identify downstream targets and signaling pathways regulated by KMT2D in PCa.

Main Methods:

• Disease-targeted sequencing was employed to profile mutations in 32 PCa-associated genes.
• KMT2D expression levels were analyzed in relation to patient prognosis using an independent cohort.
• In vitro (cell lines) and in vivo (xenograft models) experiments were conducted to assess the functional impact of KMT2D knockdown.
• Integrative analyses of RNA sequencing (RNAseq) and chromatin immunoprecipitation sequencing (ChIPseq) were performed to identify KMT2D targets.

Main Results:

• KMT2D mutations were found in a high percentage (63.04%) of Chinese PCa patients.
• Elevated KMT2D transcription correlated with poor prognosis in an independent patient cohort.
• KMT2D knockdown significantly suppressed PCa cell proliferation, invasion, and migration in vitro.
• In vivo, KMT2D depletion markedly inhibited tumor growth by 92.21%.
• Integrative analyses identified leukemia inhibitory factor receptor (LIFR) and Kruppel-like factor-4 (KLF4) as key genes downregulated by KMT2D.

Conclusions:

• KMT2D plays a significant role in prostate cancer, particularly in the Chinese population, through high mutation rates.
• KMT2D promotes PCa progression by epigenetically activating the PI3K/Akt pathway via LIFR and the epithelial-mesenchymal transition (EMT) via KLF4.
• These findings establish KMT2D as a potential epigenetic target for novel prostate cancer therapies.