黑色素瘤
丝氨酸
下调和上调
癌症研究
MAPK/ERK通路
生物
细胞生长
细胞生物学
信号转导
磷酸化
基因
遗传学
作者
Neel Jasani,Xiaonan Xu,Benjamin Posorske,Yumi Kim,Kaizhen Wang,Olga Vera,Kenneth Y. Tsai,Gina M. DeNicola,Florian A. Karreth
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-11-04
标识
DOI:10.1158/0008-5472.can-24-2471
摘要
Abstract Overexpression of PHGDH, the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. Here, we found that PHGDH is universally increased in melanoma cells and required for melanomagenesis. While PHGDH amplification explained PHGDH overexpression in a subset of melanomas, oncogenic BRAFV600E also promoted PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, depletion of PHGDH in genetic mouse melanoma models blocked tumor formation. In addition to BRAFV600E-mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAFV600E inhibition diminished serine restriction-mediated PHGDH expression by preventing ATF4 induction. Consequently, melanoma cells could be specifically starved of serine by combining BRAFV600E inhibition with exogenous serine restriction, which promoted cell death in vitro and attenuated melanoma growth in vivo. In summary, this study identified that PHGDH is essential for melanomagenesis and regulated by BRAFV600E, revealing a targetable vulnerability in BRAFV600E-mutant melanoma.
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