SIRT6-PARP1 is involved in HMGB1 polyADP-ribosylation and acetylation and promotes chemotherapy-induced autophagy in leukemia
SIRT6-PARP1 is involved in HMGB1 polyADP-ribosylation and acetylation and promotes chemotherapy-induced autophagy in leukemia
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DOI：
10.1080/15384047.2019.1702397
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发表时间：
2020-01-13
影响因子：
3.6
通讯作者：
Fang, Jianpei
中科院分区：
文献类型：
--
作者：
Kong, Qian;Li, Yunyao;Fang, Jianpei
高迁移率族盒蛋白 1 (HMGB1) 是一种进化上保守的非组蛋白染色质结合蛋白。在之前的一项研究中，我们发现用化疗药物治疗白血病细胞会导致 HMGB1 易位，HMGB1 参与自噬并最终促进白血病的化疗耐药性。然而，HMGB1 在化疗诱导的自噬中的潜在易位机制仍不清楚。在这项研究中，我们发现敲低 SIRT6 或 PARP1 基因表达可显着抑制 HMGB1 细胞质易位和自噬。同时，我们发现SIRT6是PARP1的重要上游蛋白，与PARP1相关，导致聚ADP核糖聚合酶活性的刺激。我们进一步证明，化疗诱导白血病细胞中HMGB1的ADP核糖基化需要SIRT6和PARP1激活，进而影响HMGB1的乙酰化，最终促进HMGB1易位介导的白血病细胞的自噬。这些发现为化疗耐药机制提供了新的见解。靶向 HMGB1 易位可能会克服白血病中与自噬相关的化疗耐药性。
High mobility group box protein 1 (HMGB1) is an evolutionarily conserved non-histone chromatin-binding protein. In a previous study, we showed that treating leukemic cells with chemotherapeutic drugs leads to the translocation of HMGB1, which is involved in autophagy and ultimately promotes chemoresistance in leukemia. However, the underlying translocation mechanism of HMGB1 in chemotherapy-induced autophagy remains unclear. In this study, we showed that knockdown of SIRT6 or PARP1 gene expression significantly inhibited HMGB1 cytoplasmic translocation and autophagy. Meanwhile, we found that SIRT6, an important upstream protein of PARP1, associated with PARP1, leading to the stimulation of polyADP-ribose polymerase activity. We further demonstrated that SIRT6 and PARP1 activation were required for chemotherapy-induced ADP-ribosylation of HMGB1 in leukemic cells and then influenced the acetylation of HMGB1, finally promoting the autophagy of leukemic cells mediated by HMGB1 translocation. These findings provide new insights into the mechanism of chemotherapeutic drug resistance. Targeting the HMGB1 translocation may overcome autophagy-related chemoresistance in leukemia.