Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads

Nature Communications
Shuyang ChenRutao Cui

Abstract

Some genetic melanocortin-1 receptor (MC1R) variants responsible for human red hair color (RHC-variants) are consequently associated with increased melanoma risk. Although MC1R signaling is critically dependent on its palmitoylation primarily mediated by the ZDHHC13 protein-acyl transferase, whether increasing MC1R palmitoylation represents a viable therapeutic target to limit melanomagenesis in redheads is unknown. Here we identify a specific and efficient in vivo strategy to induce MC1R palmitoylation for therapeutic benefit. We validate the importance of ZDHHC13 to MC1R signaling in vivo by targeted expression of ZDHHC13 in C57BL/6J-MC1RRHC mice and subsequently inhibit melanomagenesis. By identifying APT2 as the MC1R depalmitoylation enzyme, we are able to demonstrate that administration of the selective APT2 inhibitor ML349 treatment efficiently increases MC1R signaling and represses UVB-induced melanomagenesis in vitro and in vivo. Targeting APT2, therefore, represents a preventive/therapeutic strategy to reduce melanoma risk, especially in individuals with red hair.

References

Feb 1, 1997·Photodermatology, Photoimmunology & Photomedicine·B L DiffeyH C Wulf
May 8, 1998·Biochemical and Biophysical Research Communications·P A FrändbergV Chhájlani
Jun 23, 1998·The Journal of Biological Chemistry·J A Duncan, A G Gilman
Jul 17, 1998·The Journal of Investigative Dermatology·R SmithJ L Rees
Aug 12, 1998·The Journal of Cell Biology·C BertolottoR Ballotti
Mar 5, 1999·Biochimica Et Biophysica Acta·T ToyodaS Yamashita
Jul 15, 1999·Biochemical and Biophysical Research Communications·H B SchiöthJ L Rees
Nov 2, 2001·Human Molecular Genetics·E HealyI J Jackson
May 25, 2002·Pigment Cell Research·Kazumasa Wakamatsu, Shosuke Ito
Dec 1, 2004·The Journal of Biological Chemistry·Markus BöhmAgatha Schwarz
Feb 12, 2005·Science·Oliver RocksPhilippe I H Bastiaens
Jan 19, 2006·Genesis : the Journal of Genetics and Development·Ichiro YajimaLionel Larue
May 6, 2006·Genesis : the Journal of Genetics and Development·Marcus BosenbergLynda Chin
May 25, 2006·International Journal of Cancer. Journal International Du Cancer·Jiali HanDavid J Hunter
Feb 23, 2007·Nature·Jennifer Y Lin, David E Fisher
Feb 20, 2008·Photochemistry and Photobiology·Zalfa A Abdel-MalekRenny Starner
Mar 14, 2009·Nature Genetics·David DankortMarcus Bosenberg
Apr 7, 2009·Cancer Cell·Nathalie DhomenRichard Marais
Jun 11, 2009·Journal of Neurochemistry·Gerald R PrescottLuke H Chamberlain
Jun 30, 2009·Pigment Cell & Melanoma Research·Zalfa A Abdel-MalekJames J Knittel
Feb 10, 2010·International Journal of Cancer. Journal International Du Cancer·Catherine M OlsenDavid C Whiteman
Apr 27, 2010·Nature Chemical Biology·Frank J DekkerHerbert Waldmann
Jun 14, 2012·Journal of the American Chemical Society·Alexander AdibekianBenjamin F Cravatt
Aug 13, 2013·The Journal of Investigative Dermatology·Rachel E BellCarmit Levy
Aug 27, 2013·Molecular Cell·Juxiang CaoRutao Cui
Jul 6, 2016·Nature Chemical Biology·Baoen ChenXu Wu
Jul 13, 2016·Nature Communications·Carla Daniela Robles-EspinozaDavid J Adams
Aug 3, 2016·The Journal of Biological Chemistry·Naoko AdachiJonathan S Stamler
Jan 10, 2017·Cell Chemical Biology·Jeannie L HernandezBrent R Martin

❮ Previous
Next ❯

Citations

Dec 7, 2019·Expert Opinion on Drug Discovery·Mohamed Rasheed Gadalla, Michael Veit
Dec 25, 2019·Biochemical Society Transactions·Niall J FraserWilliam Fuller
Mar 19, 2020·The Journal of Biological Chemistry·Nataliya GorinskiEvgeni Ponimaskin
Mar 7, 2020·Frontiers in Physiology·Kobina EssandohMatthew J Brody
Apr 7, 2020·Journal of Cutaneous Pathology·Atrin ToussiMaija Kiuru
Oct 20, 2020·Pharmacology & Therapeutics·Xiaoyu TianRutao Cui
Jan 29, 2021·The FEBS Journal·Hening Lin
Oct 24, 2020·Journal of Cellular Physiology·Jiayu JinDan Meng
May 14, 2021·PloS One·Shirly FreilikhmanIrit Adini
Jun 2, 2021·The Medical Clinics of North America·Sarem Rashid, Hensin Tsao
Aug 7, 2021·Genes·Michele ManganelliGabriella Guida
Aug 8, 2021·The Journal of Investigative Dermatology·Stefania GuidaColin Ronald Goding
Aug 11, 2021·ACS Chemical Biology·Jun Young HongHening Lin

❮ Previous
Next ❯

Methods Mentioned

BETA
RNA-seq
Transgenic
PCR
immunoprecipitation
xenograft
co-immunoprecipitation
genotyping

Software Mentioned

GEPIA ( Gene Expression Profiling Interactive Analysis )

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.