PDF(Pubmed)
Abstract：
SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth, while SOX10 loss-of-function drives the emergence of therapy-resistant, invasive melanoma phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10\'s role in melanoma proliferation, while preventing a concomitant increase in tumor cell invasion. Here, we report that the lysine acetyltransferase (KAT) EP300 and SOX10 gene loci on Chromosome 22 are frequently co-amplified in melanomas, including UV-associated and acral tumors. We further show that p300 KAT activity mediates SOX10 protein stability and that the p300 inhibitor, A-485, downregulates SOX10 protein levels in melanoma cells via proteasome-mediated degradation. Additionally, A-485 potently inhibits proliferation of SOX10+ melanoma cells while decreasing invasion in AXLhigh/MITFlow melanoma cells through downregulation of metastasis-related genes. We conclude that the SOX10/p300 axis is critical to melanoma growth and invasion, and that inhibition of p300 KAT activity through A-485 may be a worthwhile therapeutic approach for SOX10-reliant tumors.
摘要：
SOX10是一种对黑色素瘤肿瘤生长至关重要的谱系特异性转录因子，而SOX10功能丧失驱动了治疗抗性的出现，侵袭性黑色素瘤表型。一个主要的挑战是开发针对SOX10在黑色素瘤增殖中的作用的治疗策略，同时防止肿瘤细胞侵袭的伴随增加。这里,我们报道，赖氨酸乙酰转移酶（KAT）EP300和SOX10基因位点在第22号染色体上经常在黑色素瘤中共同扩增，包括紫外线相关和肢端肿瘤。我们进一步表明，p300KAT活性介导SOX10蛋白的稳定性和p300抑制剂，A-485通过蛋白酶体介导的降解下调黑素瘤细胞中的SOX10蛋白水平。此外,A-485通过下调转移相关基因有效抑制SOX10+黑素瘤细胞的增殖，同时降低AXLhigh/MITFlow黑素瘤细胞的侵袭。我们得出结论，SOX10/p300轴对黑色素瘤的生长和侵袭至关重要，并且通过A-485抑制p300KAT活性可能是SOX10相关肿瘤的有价值的治疗方法。
