Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming.

in Nature cancer by Xujia Wu, Huairui Yuan, Qiulian Wu, Yixin Gao, Tingting Duan, Kailin Yang, Tengfei Huang, Shuai Wang, Fanen Yuan, Derrick Lee, Suchet Taori, Tritan Plute, Søren Heissel, Hanan Alwaseem, Michael Isay-Del Viscio, Henrik Molina, Sameer Agnihotri, Dennis J Hsu, Nu Zhang, Jeremy N Rich

TLDR

  • The study found that cancer stem cells have a different way of making proteins than normal cells. They found that a specific enzyme called YRDC is important for this process. When they stopped YRDC from working, it slowed down the cancer cells' growth and made them less able to make proteins. They also found that a dietary change called threonine restriction could help slow down the cancer cells' growth and make them more sensitive to treatment.

Abstract

Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N-threonylcarbamoyladenosine (tA) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced tA formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated tA formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor tA formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment.

Overview

  • The study investigates the coordination of translation and metabolism in cancer stem cells, specifically in glioblastoma stem cells (GSCs).
  • The hypothesis being tested is that GSCs display elevated protein translation and that YRDC, a transfer RNA (tRNA) modification enzyme, plays a crucial role in this process.

Comparative Analysis & Findings

  • The study found that GSCs have elevated protein translation compared to non-stem cells. A CRISPR screen identified YRDC as the top essential tRNA modification enzyme in GSCs. Targeting YRDC reduced tA formation, suppressed global translation, and inhibited tumor growth both in vitro and in vivo.

Implications and Future Directions

  • The study's findings suggest that YRDC plays a crucial role in the coordination of translation and metabolism in GSCs. Dietary threonine restriction (TR) reduced tumor tA formation, slowed xenograft growth, and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy. Future research could explore the use of TR as a dietary intervention in cancer treatment.
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