Carboxy-Methylation of PP2Ac Integrates Methionine Availability with Cancer Cell Proliferation

Cancer cells exhibit a well-documented, yet poorly understood, dependence on exogenous methionine, despite retaining the capacity to convert homocysteine to methionine. In contrast, non-tumorigenic cells can proliferate when methionine is replaced by homocysteine. To investigate the mechanistic basis of this methionine dependence, we examined how methionine metabolism impacts cell cycle progression. We identified carboxy-methylation of the catalytic subunit of Protein Phosphatase 2A (PP2A) as a critical node linking methionine availability to proliferation. PP2A methylation was found to be highly sensitive to intracellular S-adenosylmethionine (SAM) levels, with reduced methylation correlating with impaired proliferation under methionine restriction. Overexpression of Protein Phosphatase Methylesterase-1 (PME-1), which demethylates PP2A, or expression of a Leu309-deleted PP2A mutant that mimics the demethylated form, was sufficient to reduce proliferation even in methionine-independent cells. These findings support a model in which methionine limitation lowers SAM availability, thereby decreasing PP2A methylation and impairing cell cycle progression. Our study reveals a novel mechanistic link between methionine metabolism and the cell cycle and suggests that PP2A methylation plays a key role in the unique methionine dependence of cancer cells. HEK293T and R1 cells were cultured in either +Met or -Met+Hcy media for 12 hours and total RNA was extracted using kit (Qiagen, 74104). Samples were then sent to Novogene Corporation Inc. for library preparation and sequencing (Sacramento, CA, USA).