Lcmt1, or Leucine carboxyl methyltransferase 1, is a protein methyltransferase. It transfers a methyl group from S-adenosylmethionine to the catalytic subunits of Protein Phosphatase 2A (PP2Ac), PP4 and PP6. This post-translational modification is crucial as it regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity [4]. PP2A is involved in many cellular processes, so Lcmt1 is essential for normal cell function. Genetic models, like KO/CKO mouse models, are valuable for studying Lcmt1's functions.

In prostate cancer, silencing Lcmt1 in mouse models increases androgen receptor (AR) activity and promotes castration-resistant prostate cancer growth. Lcmt1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its co-activator MED1 for dephosphorylation, leading to eviction of the AR-MED1 complex from chromatin and loss of target gene expression [1]. In a liver-specific lcmt1 knockout (L-LCMT1 KO) mouse model, low-dose benzo[a]pyrene-induced hepatic lipid deposition was shown to be regulated through Lcmt1-mediated PP2Ac methylation, as L-LCMT1 KO mice had altered lipid deposition patterns [2]. In hepatocellular carcinoma (HCC), siRNA-mediated knockdown of Lcmt1 in vitro and in mouse xenograft models inhibited cell proliferation, glycolysis, promoted mitochondrial dysfunction, and increased intracellular pyruvate levels [3].

In conclusion, Lcmt1 is vital for normal cellular function through its role in PP2A methylation. Studies using KO/CKO mouse models have revealed its significance in diseases such as prostate cancer, hepatic lipid deposition-related disorders, and HCC. These models have provided insights into the molecular mechanisms by which Lcmt1 influences these disease processes, potentially guiding the development of novel therapeutic strategies.