Sirt2-associated transcriptome modifications in cisplatin-induced neuronal injury

Abstract

Background: Chemotherapy-induced peripheral neuropathy is not only one of the most common causes of dose reduction or discontinuation of cancer treatment, but it can also permanently decrease the quality of life of cancer patients and survivors. Notably, Sirt2 protects many organs from various injuries, including diabetic peripheral neuropathy. As demonstrated previously by our laboratory and others, the overexpression of Sirt2 can improve cisplatin-induced neuropathy, although the mechanism is still unclear. Results: In this study, the underlying mechanism by which Sirt2 protects neurons from cisplatin-induced injury was explored using the RNAseq technique in cultured rodent neurons. Sirt2 status was modified by genetic knockout (Sirt2/KO) and was then reconstituted in Sirt2/KO cells (Sirt2/Res). We observed 323 upregulated genes and 277 downregulated genes in Sirt2-expressing cells (Sirt2/Res) compared to Sirt2-deficient cells (Sirt2/KO). Pathway analysis suggested that Sirt2 may affect several pathways, such as MAPK, TNF, and cytokine-cytokine interaction. Furthermore, cisplatin-induced changes to the transcriptome are strongly associated with Sirt2 status. Cisplatin induced distinctive transcriptome changes for 227 genes in Sirt2-expressing cells and for 783 genes in Sirt2-deficient cells, while changes in only 138 of these genes were independent of Sirt2 status. Interestingly, changes in the p53 pathway, ECM-receptor interactions, and cytokine-cytokine receptor interactions were induced by cisplatin only in Sirt2-deficient cells. Conclusions: This study demonstrated that Sirt2 regulates the transcriptome in cultured rodent neuronal cells. Furthermore, Sirt2-associated transcriptome regulation may be an important mechanism underlying the role of Sirt2 in organ protection, such as in cisplatin-induced neuronal injury. Sirt2 may be a potential target for the prevention and treatment of chemotherapy-induced neuropathy.

SIRT2 inhibition exacerbates p53-mediated ferroptosis in mice following experimental traumatic brain injury

“…Furthermore, acetylation is crucial for p53-mediated ferroptosis [4]. SIRT2 exerts its biological effect by deacetylating p53 [8,25]. In the present study, our findings suggest that the SIRT2 inhibits ferroptosis by deacetylating and downregulating p53.…”

Dietary Supplements in Chemotherapy-Induced Peripheral Neuropathy: A New Hope?

“…Some evidence states that SIRT2 accumulates in the nuclei of dorsal root ganglion sensory neurons and the protection of peripheral neurons against cisplatin is possible through its activation [ 161 ]. Zhao et al [ 162 ] described that SIRT2 may have an impact on the pathways like MAPK, TNF, or the cytokine-cytokine interaction, which was a result of RNAseq technique usage in cultured rodent neurons. Cisplatin-induced changes were proven to depend on SIRT2 status, with 783 affected genes measured in SIRT2-deficient cells and 227 affected genes in the SIRT-2-expressing cells, therefore indicating SIRT2 presence to regulate the response to cisplatin [ 162 ].…”

“…Zhao et al [ 162 ] described that SIRT2 may have an impact on the pathways like MAPK, TNF, or the cytokine-cytokine interaction, which was a result of RNAseq technique usage in cultured rodent neurons. Cisplatin-induced changes were proven to depend on SIRT2 status, with 783 affected genes measured in SIRT2-deficient cells and 227 affected genes in the SIRT-2-expressing cells, therefore indicating SIRT2 presence to regulate the response to cisplatin [ 162 ]. To the best of authors’ knowledge, no clinical trials investigating the feasibility of using SIRT2 as an ameliorative factor in CIPN have been performed to this day.…”

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy

“…Besides revealing direct effects on the immune cells and cytokines production, OHP and CDDP may affect inflammatory compartment modulating gene expression. In particular, it has been reported that CDDP may affect the expression of genes implicated in neuroinflammatory processes such as TNF-α and cytokine-cytokine interactions pathways in cultured rat sensory neuron-like cells ( 32 ). In agreement with these findings, the transcriptome analysis of lumbar DRG of CDDP-treated mice revealed changes in the expression of genes involved in both neuronal damage and inflammatory processes ( 33 ).…”