Slow Proliferation of BAP1-Deficient Uveal Melanoma Cells Is Associated With Reduced S6 Signaling and Resistance to Nutrient Stress

Authors

Vivian Chua
Melisa Lopez-Anton
Mizue Terai
Ryota Tanaka
Usman Baqai
Timothy J Purwin
Jelan I Haj
Francis J Waltrich
Isabella Trachtenberg
Kristine Luo
Rohith Tudi
Angela Jeon
Anna Han
Inna Chervoneva
Michael A Davies
Julio A Aguirre-Ghiso
Takami Sato
Andrew E Aplin

Publication Date

6-11-2024

Journal

Science Signaling

Abstract

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings, BAP1 mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in BAP1 mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.

Keywords

Animals, Humans, Mice, Cell Line, Tumor, Cell Proliferation, Melanoma, Mutation, Phosphorylation, Ribosomal Protein S6, Signal Transduction, Stress, Physiological, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, Uveal Neoplasms, Female, Uveal Melanoma

DOI

10.1126/scisignal.adn8376

PMID

38861613

PMCID

PMC11328427

PubMedCentral® Posted Date

12-11-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes