Kong Sun-Hyok, Ma Lie, Yuan Qingxia, Liu Xiangxiang, Han Yu, Xiang Weifang, Liu Dong-Xu, Zhang Yu, Lu Jun
The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, 130024, China.
School of Life Science, University of Science, Pyongyang, 999091, Democratic People's Republic of Korea.
Cell Death Discov. 2023 Aug 5;9(1):289. doi: 10.1038/s41420-023-01591-y.
Chemotherapy has been widely used in small cell lung cancer (SCLC) treatment in the past decades. However, SCLC is easy to recur after chemotherapy. The senescence of cancer cells during chemotherapy is one of the effective therapeutic strategies to inhibit the progression of cancer. Nevertheless, the senescence-associated secretion phenotype (SASP) promotes chronic inflammation of the cancer microenvironment and further accelerates the progression of tumors. Therefore, inducing the senescence of cancer cells and inhibiting the production of SASP factors during anticancer treatment have become effective therapeutic strategies to improve the anticancer effect of drugs. Here we reported that SCLC cells treated with an FDA-approved HDAC inhibitor SAHA underwent senescence and displayed remarkable SASP. In particular, SAHA promoted the formation of cytoplasmic chromatin fragments (CCFs) in SCLC cells. The increased CCFs in SAHA-treated SCLC cells were related to nuclear porin Tpr, which activated the cGAS-STING pathway, and promoted the secretion of SASP in cancer cells. Inhibition of EZH2 suppressed the increase of CCFs in SAHA-treated SCLC cells, weakened the production of SASP, and increased the antiproliferative effect of SAHA. Overall, our work affords new insight into the secretion of SASP in SCLC and establishes a foundation for constructing a new therapeutic strategy for SCLC patients.
在过去几十年中，化疗已广泛应用于小细胞肺癌（SCLC）的治疗。然而，SCLC在化疗后很容易复发。化疗期间癌细胞的衰老 是抑制癌症进展的有效治疗策略之一。然而，衰老相关分泌表型（SASP）会促进癌症微环境的慢性炎症，并进一步加速肿瘤的进展。因此，在抗癌治疗过程中诱导癌细胞衰老并抑制SASP因子的产生已成为提高药物抗癌效果的有效治疗策略。在此，我们报道了用美国食品药品监督管理局（FDA）批准的组蛋白去乙酰化酶（HDAC）抑制剂SAHA处理的SCLC细胞会发生衰老并表现出显著的SASP。特别是，SAHA促进了SCLC细胞中细胞质染色质片段（CCF）的形成。SAHA处理的SCLC细胞中CCF的增加与核孔蛋白Tpr有关，Tpr激活了环鸟苷酸-腺苷酸合成酶-干扰素基因刺激蛋白（cGAS-STING）途径，并促进了癌细胞中SASP的分泌。抑制EZH2可抑制SAHA处理的SCLC细胞中CCF的增加，减弱SASP的产生，并增强SAHA的抗增殖作用。总的来说，我们的工作为深入了解SCLC中SASP的分泌提供了新的见解，并为构建针对SCLC患者的新治疗策略奠定了基础。
