# PMM2 interacts with TRIM28 to recruit E2F4 and promote KIFC3-mediated tumor glycolysis and colorectal cancer progression

## TL;DR

PMM2 promotes colorectal cancer by interacting with TRIM28 and E2F4 to enhance glycolysis and tumor growth.

## Contribution

PMM2 is identified as a novel oncogenic driver in CRC through its role in metabolic reprogramming and tumor progression.

## Key findings

- PMM2 is upregulated in CRC and correlates with poor patient survival and advanced tumor stages.
- PMM2 interacts with TRIM28 and recruits E2F4 to enhance KIFC3 transcription and glycolytic activity.
- KIFC3 mediates PMM2-driven glycolysis and tumor growth in xenograft models.

## Abstract

Colorectal cancer (CRC) remains a major global health burden with limited therapeutic options. This study identifies phosphomannomutase 2 (PMM2) as a key oncogenic driver in CRC. PMM2 is significantly upregulated in CRC tissues and cell lines, correlating with advanced tumor stages, lymphatic metastasis, and poor patient survival. Functional assays reveal that PMM2 knockdown inhibits CRC cell proliferation, migration, invasion, and glycolytic activity (reducing glucose uptake, ATP/lactate production, and extracellular acidification rate). Mechanistically, PMM2 interacts with transcriptional regulator TRIM28, promoting TRIM28 nuclear translocation, recruiting transcription factor E2F4, and enhancing KIFC3 transcription by binding to its promoter. KIFC3 mediates PMM2-driven glycolysis, as KIFC3 knockdown partially reverses PMM2-induced metabolic reprogramming and tumor growth in xenograft models. Patient-derived organoid studies further confirm PMM2’s role in promoting CRC progression through the PMM2-KIFC3 axis. Collectively, these findings establish PMM2 as a prognostic biomarker and potential therapeutic target in CRC, highlighting its critical role in metabolic reprogramming and tumorigenesis.