SIRT6-PARP1 is involved in HMGB1 polyADP-ribosylation and acetylation and promotes chemotherapy-induced autophagy in leukemia

Abstract

High mobility group box protein 1 (HMGB1) is an evolutionarily conserved non-histone chromatinbinding 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.

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

“…Recently, the poly-ADP-ribosylation of HMGB1 was found to facilitate its acetylation and promoted HMGB1 translocation-associated chemotherapy-induced autophagy in leukemia cells [ 22 ]. The activation of SIRT6 and PARP1 is required for chemotherapy-induced ADP-ribosylation of HMGB1 and mediates HMGB1 translocation [ 23 ]. Hyperpoly-ADP-ribosylation of HMGB1 enhances the inhibition of efferocytosis, but a lack of intracellular HMGB1 leads to excessive activation and damage of PARP1 [ 24 , 25 ].…”

Emerging roles of SIRT6 in human diseases and its modulators

“…However, SIRT6 may also promote the invasiveness of ovarian cancer cells via activation of EMT‐related signaling pathway 118 . The role of SIRT6 is controversial and not well understood in leukemia 120,121,136,136,137 . A typical biological relevance comparison from Cagnetta et al observed that acute myeloid leukemia (AML) patients with SIRT6 overexpression showed features of genomic instability and poor prognosis, and SIRT6‐KD made AML blasts more sensitive to daunorubicin treatment in NSG mice.…”

Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma

“…Based on these paradoxical roles of the molecules of the DNA damage repair pathway, inhibitors of this pathway, such as Poly (ADP-ribose) polymerase (PARP) inhibitors, have been developed as anti-cancer agents [11,21]. Therefore, when based on the role of SIRT6 in the DNA damage repair pathway [1,8,25], SIRT6 might be an inducer of therapeutic resistance [26].…”

“…Furthermore, the role of SIRT6 in the progression of osteosarcoma has been reported controversially [ 32 , 33 , 35 ]. However, when considering the role of SIRT6 in the repair of DNA damage, SIRT6 might be involved in the effectiveness of anti-cancer treatment [ 2 , 8 , 25 , 26 , 29 ]. Therefore, this study evaluated the role and effect of SIRT6 expression on osteosarcoma by investigating the expression of SIRT6 in human osteosarcomas and assessing the role of SIRT6 in resistance to the treatment of doxorubicin in conjunction with the role of SIRT6 on the repair of DNA damage.…”