DEPTOR suppresses lymphomagenesis by promoting EGFR degradation via HUWE1 E3 ligase.

in Cell death and differentiation by Xiufang Xiong, Xiaoyu Chen, Shengpeng Shao, Danrui Cui, Ruirui Qu, Baohui Wang, Ying Ma, Hui Pan, Yi Sun, Yongchao Zhao

TLDR

  • DEPTOR, a naturally occurring inhibitor of mTOR, is a tumor suppressor that inhibits lymphomagenesis in the context of Pten-loss.
  • Knocking out DEPTOR accelerates lymphomagenesis, while degrading-resistant variants inhibit it.
  • Reactivating DEPTOR could be a promising approach for lymphoma treatment

Abstract

DEPTOR, a naturally occurring inhibitor of mTOR, plays crucial roles in tumorigenesis and is frequently dysregulated in a variety of human cancers. Interestingly, DEPTOR could act either as a tumor suppressor or as an oncogene in a manner dependent of cellular context or tissue environment. Whether and how DEPTOR regulates lymphomagenesis remains elusive. In this study, we report that in a mouse lymphoma model induced by heterozygous Pten loss, Deptor knockout (KO) markedly accelerates lymphomagenesis, whereas degradation-resistant Deptorknock-in (KI) variant significantly inhibits it. Furthermore, Deptor KO mice spontaneously developed lymphomas in the later stages of their lifespan, and Deptor KO further shortened overall lifespan in Pten;MMTV-Cre mice. Consistently, DEPTOR protein levels are significantly lower in human lymphoma tissues, as compared to normal lymph nodes. Mechanistically, DEPTOR, on one hand, enhances the interaction of EGFR to HUWE1 E3 ubiquitin ligase for targeted ubiquitination and proteasomal degradation, and subsequent inactivation of the MAPK signal. On the other hand, DEPTOR inactivates both mTORC1 and mTORC2 signals. Collectively, our study demonstrated that DEPTOR is a tumor suppressor that inhibits lymphomagenesis upon Pten-loss. The strategy that reactivates DEPTOR could be a promising approach for the treatment of lymphoma.

Overview

  • This study investigated the role of DEPTOR, a naturally occurring inhibitor of mTOR, in lymphomagenesis.
  • DEPTOR was found to have dual functions as both a tumor suppressor and an oncogene, depending on the cellular context and tissue environment.
  • The study aimed to determine the effects of DEPTOR on lymphomagenesis in a mouse model and to explore its potential therapeutic applications.

Comparative Analysis & Findings

  • In a mouse lymphoma model induced by heterozygous Pten loss, Deptor knockout (KO) accelerated lymphomagenesis, whereas degradation-resistant Deptorknock-in (KI) variant inhibited it.
  • Deptor KO mice spontaneously developed lymphomas in the later stages of their lifespan, and Deptor KO further shortened overall lifespan in Pten;MMTV-Cre mice.
  • DEPTOR protein levels were significantly lower in human lymphoma tissues compared to normal lymph nodes.

Implications and Future Directions

  • The study demonstrated that DEPTOR is a tumor suppressor that inhibits lymphomagenesis in the context of Pten-loss.
  • The findings suggest that reactivating DEPTOR could be a promising approach for the treatment of lymphoma.
  • Future studies could focus on exploring the molecular mechanisms underlying DEPTOR's dual functions and developing strategies to reconstitute DEPTOR activity in lymphoma treatment
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