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Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma

Sainero-Alcolado, Lourdes ; Garde-Lapido, Elisa ; Snaebjörnsson, Marteinn Thor ; Schoch, Sarah LU ; Stevens, Irene ; Ruiz-Pérez, María Victoria ; Dyrager, Christine ; Pelechano, Vicent ; Axelson, Håkan LU and Schulze, Almut , et al. (2024) In Proceedings of the National Academy of Sciences of the United States of America 121(7). p.2310479121-2310479121
Abstract

Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven... (More)

Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
clear cell renal cell carcinoma, glutamine, HILPDA, lipid droplets, MYC
in
Proceedings of the National Academy of Sciences of the United States of America
volume
121
issue
7
pages
2310479121 - 2310479121
publisher
National Academy of Sciences
external identifiers
  • pmid:38335255
  • scopus:85184732071
ISSN
1091-6490
DOI
10.1073/pnas.2310479121
language
English
LU publication?
yes
id
649deff4-7b3a-422b-8dbe-c574de12ea9d
date added to LUP
2024-03-12 14:46:30
date last changed
2024-04-23 19:21:10
@article{649deff4-7b3a-422b-8dbe-c574de12ea9d,
  abstract     = {{<p>Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.</p>}},
  author       = {{Sainero-Alcolado, Lourdes and Garde-Lapido, Elisa and Snaebjörnsson, Marteinn Thor and Schoch, Sarah and Stevens, Irene and Ruiz-Pérez, María Victoria and Dyrager, Christine and Pelechano, Vicent and Axelson, Håkan and Schulze, Almut and Arsenian-Henriksson, Marie}},
  issn         = {{1091-6490}},
  keywords     = {{clear cell renal cell carcinoma; glutamine; HILPDA; lipid droplets; MYC}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{7}},
  pages        = {{2310479121--2310479121}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma}},
  url          = {{http://dx.doi.org/10.1073/pnas.2310479121}},
  doi          = {{10.1073/pnas.2310479121}},
  volume       = {{121}},
  year         = {{2024}},
}