TRIM65 determines the fate of a novel subtype of pituitary neuroendocrine tumors via ubiquitination and degradation of TPIT.

Abstract

BACKGROUND:

Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that are classified into seven histological subtypes, including lactotroph, somatotroph, corticotroph, thyrotroph, gonadotroph, null cell, and plurihormonal PitNETs. However, the molecular characteristics of these types of PitNETs are not completely clear.

METHODS:

A total of 180 consecutive cases of PitNETs were collected to perform RNA sequencing. All subtypes of PitNETs were distinguished by unsupervised clustering analysis. We investigated the regulation of TPIT by TRIM65 and its effects on ACTH production and secretion in ACTH-secreting pituitary cell lines, as well as in murine models using biochemical analyses, confocal microscopy, and luciferase reporter assays.

RESULTS:

A novel subtype of PitNETs derived from TPIT lineage cells was identified as with normal TPIT transcription but with lowered protein expression. Furthermore, for the first time, TRIM65 was identified as the E3 ubiquitin ligase of TPIT. Depending on the RING domain, TRIM65 ubiquitinated and degraded the TPIT protein at multiple Lys sites. In addition, TRIM65-mediated ubiquitination of TPIT inhibited POMC transcription and ACTH production to determine the fate of the novel subtype of PitNETs in vitro and in vivo.

CONCLUSION:

Our studies provided a novel classification of PitNETs and revealed that the TRIM65-TPIT complex controlled the fate of the novel subtype of PitNETs, which provides a potential therapy target for Cushing's disease.

• Authors: Hong Yao, Wanqun Xie, Yuting Dai, Yanting Liu, Weiting Gu, Jianfeng Li, Liang Wu, Jing Xie, Weiwei Rui, Bohan Ren, Li Xue, Yijun Cheng, Shaojian Lin, Changsheng Li, Hao Tang, Yu Wang, Meiqing Lou, Xiaobiao Zhang, Ronggui Hu, Hanbing Shang, Jinyan Huang, Zhe Bao Wu
• Journal: Neuro-oncology (Neuro Oncol) Vol. 24 Issue 8 Pg. 1286-1297 (08 01 2022) ISSN: 1523-5866 [Electronic] England
• PMID: 35218667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Homeodomain Proteins
• T-Box Domain Proteins
• TBX19 protein, human
• Tripartite Motif Proteins
• Adrenocorticotropic Hormone
• Ubiquitin-Protein Ligases
• TRIM65 protein, human

Topics

• Adrenocorticotropic Hormone (genetics, metabolism)
• Animals
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Mice
• Neuroendocrine Tumors (pathology)
• Pituitary ACTH Hypersecretion
• Pituitary Neoplasms (metabolism)
• T-Box Domain Proteins (genetics, metabolism)
• Tripartite Motif Proteins (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination