Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation.
Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation.
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DOI：
10.1016/j.molonc.2015.04.002
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发表时间：
2015-08
影响因子：
6.6
通讯作者：
Villagra A
中科院分区：
文献类型：
--
作者：
Woan KV;Lienlaf M;Perez-Villaroel P;Lee C;Cheng F;Knox T;Woods DM;Barrios K;Powers J;Sahakian E;Wang HW;Canales J;Marante D;Smalley KSM;Bergman J;Seto E;Kozikowski A;Pinilla-Ibarz J;Sarnaik A;Celis E;Weber J;Sotomayor EM;Villagra A
转移性黑色素瘤的中位生存期在8-16个月的范围内，并且很少有疗法能显著改善总生存期。癌症治疗的最新进展之一集中在表观遗传修饰剂上，以改变癌细胞的存活性和免疫原性。我们的小组和其他人以前已经证明，泛HDAC抑制剂诱导细胞凋亡，细胞周期停滞和黑色素瘤细胞免疫原性的变化。在这里，我们询问了可能导致这种效应的特定HDAC。我们发现，HDAC 6的遗传废除和药理学抑制降低体外增殖，诱导黑色素瘤细胞系的G1期阻滞，而不诱导凋亡。此外，靶向该分子导致肿瘤相关抗原和MHC I类表达的重要上调，表明这些细胞的免疫原性的潜在改善。值得注意的是，无论细胞的突变状态如何，这种抗黑素瘤活性都是有效的。这些作用转化为体内黑色素瘤肿瘤生长的显著延迟，这至少部分依赖于完整的免疫力，如CD 4+和CD 8+耗竭后肿瘤生长的恢复所证明的。鉴于我们的研究结果，我们为进一步开发选择性HDAC 6抑制剂作为潜在的治疗性抗黑色素瘤药物提供了初步的理论基础。
The median survival for metastatic melanoma is in the realm of 8–16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.