Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

TLDR

Metabolic reprogramming is a hallmark of cancer, yet the mechanisms regulating it are poorly understood and MYC inhibitors have long been sought. Using multiomics analysis of paired normal–tumor colorectal tissues, the study shows MYC drives global metabolic reprogramming by modulating 215 reactions, and that silencing MYC‑dependent pyrimidine synthesis genes suppresses tumor cell proliferation, highlighting pyrimidine synthesis as a therapeutic target. The study finds that MYC‑driven metabolic reprogramming in colorectal cancer occurs independently of specific gene mutations and that targeting MYC‑dependent pyrimidine synthesis genes effectively inhibits tumor cell proliferation.

Abstract

Significance Metabolic reprogramming is one of the hallmarks of cancer. However, the underlying mechanisms that regulate cancer metabolism are poorly understood. Here we performed multiomics-based analysis of paired normal–tumor tissues from patients with colorectal cancer, which revealed that the protooncogene protein MYC regulated global metabolic reprogramming of colorectal cancer by modulating 215 metabolic reactions. Importantly, this metabolic reprogramming occurred in a manner not associated with specific gene mutations in colorectal carcinogenesis. For many years, small-molecule or biologic inhibitors of MYC have been required. Here we demonstrate that knockdown of MYC downstream pyrimidine synthesis genes contributes to the suppression of colorectal cancer cell proliferation similar to MYC, and thus pyrimidine synthesis pathways could be potential targets for colorectal cancer therapy.