Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention. Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment. Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.

中文翻译：

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靶向甲基转移酶 SETD8 会损害肿瘤细胞存活并克服与多发性骨髓瘤中 p53 状态无关的耐药性

多发性骨髓瘤 (MM) 是一种浆细胞恶性肿瘤，在很大程度上仍然无法治愈。因此，寻找新的治疗靶点至关重要。除了广泛的基因突变外，表观遗传改变也似乎是这种癌症发展的重要参与者，从而为揭示有效治疗干预的新方法和靶点提供了可能性。在这里，我们表明赖氨酸甲基转移酶 SETD8 的较高表达是导致组蛋白 H4 在赖氨酸 20 处单甲基化的原因，是与两组新诊断患者的不良预后相关的不良预后因素。原发性恶性浆细胞特别沉迷于这种表观遗传酶的活性。确实，与来自骨髓微环境的正常细胞相比，化合物 UNC-0379 对 SETD8 的抑制以及随后赖氨酸 20 组蛋白 H4 甲基化的降低在 MM 细胞中具有高毒性。在分子水平上，RNA 测序和功能研究表明，SETD8 抑制诱导成熟的非增殖浆细胞特征，并且正如在其他癌症中观察到的那样，触发肿瘤抑制因子 p53 的激活，这共同导致骨髓瘤细胞增殖受损和生存。然而，在用 UNC-0379 处理的 p53 缺陷型骨髓瘤细胞中也观察到了致命的复制应激水平，这表明与 SETD8 抑制相关的细胞毒性不一定依赖于 p53 的激活。与此一致，UNC-0379 触发不依赖 p53 的核仁应激，其特征是核仁蛋白离域和核仁 RNA 合成减少。最后，我们证明了 SETD8 抑制与美法仑有很强的协同作用，并且可以克服对这种广泛用于 MM 治疗的烷化剂的抗性。总之，我们的数据表明，表观遗传酶 SETD8 的上调与不良结果和 MM 中主要信号通路的失调有关。此外，我们提供的证据表明，骨髓瘤细胞依赖于 SETD8 活性，其药理抑制作用与美法仑协同作用，这可能有助于改善高危患者的 MM 治疗，无论其 p53 状态如何。我们表明，SETD8 抑制与美法仑有很强的协同作用，并且可以克服对这种广泛用于 MM 治疗的烷化剂的抗性。总之，我们的数据表明，表观遗传酶 SETD8 的上调与不良结果和 MM 中主要信号通路的失调有关。此外，我们提供的证据表明，骨髓瘤细胞依赖于 SETD8 活性，其药理抑制作用与美法仑协同作用，这可能有助于改善高危患者的 MM 治疗，无论其 p53 状态如何。我们表明，SETD8 抑制与美法仑有很强的协同作用，并且可以克服对这种广泛用于 MM 治疗的烷化剂的抗性。总之，我们的数据表明，表观遗传酶 SETD8 的上调与不良结果和 MM 中主要信号通路的失调有关。此外，我们提供的证据表明，骨髓瘤细胞依赖于 SETD8 活性，其药理抑制作用与美法仑协同作用，这可能有助于改善高危患者的 MM 治疗，无论其 p53 状态如何。