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

Sainero-Alcolado, Lourdes (author)
Karolinska Institutet,Karolinska Institute,Department of Microbiology, Tumor and Cell Biology, Biomedicum B7, Karolinska Institutet, Stockholm 17165, Sweden
Garde-Lapido, Elisa (author)
Karolinska Institutet,Karolinska Institute,Department of Microbiology, Tumor and Cell Biology, Biomedicum B7, Karolinska Institutet, Stockholm 17165, Sweden
Snaebjörnsson, Marteinn Thor (author)
Division of Tumor Metabolism and Microenvironment, German Cancer Research Center, Heidelberg 69120, Germany
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Schoch, Sarah (author)
Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Njurcancergruppen,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Kidney cancer research group,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund 22100, Sweden
Stevens, Irene (author)
Karolinska Institutet,Karolinska Institute,Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 17165, Sweden
Ruiz-Pérez, María Victoria (author)
Karolinska Institute,Department of Microbiology, Tumor and Cell Biology, Biomedicum B7, Karolinska Institutet, Stockholm 17165, Sweden
Dyrager, Christine (author)
Uppsala universitet,Uppsala University,Organisk kemi
Pelechano, Vicent (author)
Karolinska Institutet,Karolinska Institute,Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 17165, Sweden
Axelson, Håkan (author)
Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Njurcancergruppen,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Kidney cancer research group,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund 22100, Sweden
Schulze, Almut (author)
Division of Tumor Metabolism and Microenvironment, German Cancer Research Center, Heidelberg 69120, Germany
Arsenian-Henriksson, Marie (author)
Karolinska Institutet,Karolinska Institute,Department of Microbiology, Tumor and Cell Biology, Biomedicum B7, Karolinska Institutet, Stockholm 17165, Sweden
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Proceedings of the National Academy of Sciences (PNAS), 2024
2024
English.
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 121:7, s. 2310479121-2310479121
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

Keyword

clear cell renal cell carcinoma
glutamine
HILPDA
lipid droplets
MYC

Publication and Content Type

art (subject category)
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