Dual Inhibition of H3K9me2 and H3K27me3 Promotes Tumor Cell Senescence without Triggering the Secretion of SASP.
Dual Inhibition of H3K9me2 and H3K27me3 Promotes Tumor Cell Senescence without Triggering the Secretion of SASP.
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H3K9me2 和 H3K27me3 的双重抑制促进肿瘤细胞衰老而不触发 SASP 的分泌
DOI：
10.3390/ijms23073911
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发表时间：
2022-04-01
影响因子：
5.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhang N;Shang M;Li H;Wu L;Dong M;Huang B;Lu J;Zhang Y
化疗仍然是最常见的癌症治疗。虽然化疗药物诱导肿瘤细胞衰老，但它们通常通过诱导衰老相关分泌表型（SASP）而与治疗后肿瘤复发相关。因此，重要的是确定有效的策略来诱导肿瘤细胞衰老而不触发SASP。在这项研究中，我们使用小分子抑制剂，UNC 0642（G9 a抑制剂）和UNC 1999（EZH 2抑制剂）单独或联合使用，以抑制不同癌细胞中的H3 K9和H3 K27甲基化。在高转移性肿瘤细胞中H3 K9 me 2和H3 K27 me 3的双重抑制比单独的任一抑制剂具有更强的促衰老作用，并且在肿瘤细胞中不触发SASP。H3 K9 me 2和H3 K27 me 3的双重抑制抑制了胞质染色质片段的形成，这抑制了cGAS-STING-SASP途径。总的来说，这些数据表明，H3 K9和H3 K27甲基化的双重抑制可以诱导高转移性肿瘤细胞衰老，而不会通过抑制cGAS-STING-SASP途径触发SASP，为针对H3 K9和H3 K27甲基化的表观遗传学治疗提供了新的机制。
Chemotherapy remains the most common cancer treatment. Although chemotherapeutic drugs induce tumor cell senescence, they are often associated with post-therapy tumor recurrence by inducing the senescence-associated secretory phenotype (SASP). Therefore, it is important to identify effective strategies to induce tumor cell senescence without triggering SASP. In this study, we used the small molecule inhibitors, UNC0642 (G9a inhibitor) and UNC1999 (EZH2 inhibitor) alone or in combination, to inhibit H3K9 and H3K27 methylation in different cancer cells. Dual inhibition of H3K9me2 and H3K27me3 in highly metastatic tumor cells had a stronger pro-senescence effect than either inhibitor alone and did not trigger SASP in tumor cells. Dual inhibition of H3K9me2 and H3K27me3 suppressed the formation of cytosolic chromatin fragments, which inhibited the cGAS-STING-SASP pathway. Collectively, these data suggested that dual inhibition of H3K9 and H3K27 methylation induced senescence of highly metastatic tumor cells without triggering SASP by inhibiting the cGAS-STING-SASP pathway, providing a new mechanism for the epigenetics-based therapy targeting H3K9 and H3K27 methylation.
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染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
3.3
作者：
Freund A;Laberge RM;Demaria M;Campisi J
通讯作者：
Campisi J
EZH2-CCF-cGAS轴促进乳腺癌转移
影响因子：
5.6
作者：
Duan D;Shang M;Han Y;Liu J;Liu J;Kong SH;Hou J;Huang B;Lu J;Zhang Y
通讯作者：
Zhang Y
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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