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.

中文翻译：

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MAPK 诱导 PHGDH 对于黑色素瘤的形成至关重要，并会产生可操作的代谢脆弱性


PHGDH 是丝氨酸合成途径中的限速酶，其过表达可促进黑色素瘤发生、黑色素瘤细胞增殖和转移瘤在低丝氨酸环境（如大脑）中的存活。在这里，我们发现 PHGDH 在黑色素瘤细胞中普遍增加，并且是黑色素瘤发生所必需的。虽然 PHGDH 扩增解释了 PHGDH 在黑色素瘤亚群中的过表达，但致癌BRAFV600E也通过 mTORC1 介导的 ATF4 翻译促进了 PHGDH 转录。重要的是，遗传小鼠黑色素瘤模型中 PHGDH 的耗竭阻断了肿瘤的形成。除了 BRAFV600E 介导的上调外，PHGDH 还被外源性丝氨酸限制进一步诱导。令人惊讶的是，BRAFV600E抑制通过阻止 ATF4 诱导降低了丝氨酸限制介导的 PHGDH 表达。因此，通过将BRAFV600E抑制与外源性丝氨酸限制相结合，黑色素瘤细胞可以特异性地缺乏丝氨酸，从而促进体外细胞死亡并减弱体内黑色素瘤生长。总之，本研究确定 PHGDH 对黑色素瘤发生至关重要并受 BRAFV600E 调节，揭示了 BRAFV600E 突变黑色素瘤中的可靶向脆弱性。