Sirtuins Affect Cancer Stem Cells via Epigenetic Regulation of Autophagy

Abstract

Sirtuins (SIRTs) are stress-responsive proteins that regulate several post-translational modifications, partly by acetylation, deacetylation, and affecting DNA methylation. As a result, they significantly regulate several cellular processes. In essence, they prolong lifespan and control the occurrence of spontaneous tumor growth. Members of the SIRT family have the ability to govern embryonic, hematopoietic, and other adult stem cells in certain tissues and cell types in distinct ways. Likewise, they can have both pro-tumor and anti-tumor effects on cancer stem cells, contingent upon the specific tissue from which they originate. The impact of autophagy on cancer stem cells, which varies depending on the specific circumstances, is a very intricate phenomenon that has significant significance for clinical and therapeutic purposes. SIRTs exert an impact on the autophagy process, whereas autophagy reciprocally affects the activity of certain SIRTs. The mechanism behind this connection in cancer stem cells remains poorly understood. This review presents the latest findings that position SIRTs at the point where cancer cells and autophagy interact. Our objective is to highlight the various roles of distinct SIRTs in cancer stem cell-related functions through autophagy. This would demonstrate their significance in the genesis and recurrence of cancer and offer a more precise understanding of their treatment possibilities in relation to autophagy.

Keywords: DNA methylation; SIRT; acetylation; autophagy; cancer stem cells; deacetylation; epigenetics; sirtuins.

Figure 1

Intracellular location and main enzymatic activities of SIRTs. The figure was partly created with BioRender.com.

Figure 2

The role of the SIRT1–c-Myc axis in the control of stem cells. Both SIRT1 and c-Myc have significant expression levels in several types of stem cells. SIRT1 removes acetyl groups from c-Myc, leading to enhanced stability. When c-Myc is more stable, it increases the transcription of c-Myc target genes like Usp22, Mat2a, Tert, and Smpdl3b. The upregulation of MAT2A leads to the synthesis of SAM, resulting in an elevation of H3K4me3 levels on pluripotent genes and subsequently promoting their expression. This activity is crucial for the preservation of pluripotent stem cells. C-Myc also stimulates the production of SMPDL3B to modify sphingolipids on the plasma membrane, affecting the flexibility of the membrane and the signaling pathways which are involved in the process of neuronal development. C-Myc stimulates the process of transcribing Tert, which, in turn, enhances the elongation of telomeres. C-Myc enhances the excessive production of USP22, an enzyme which removes ubiquitin from proteins, leading to the stabilization of SIRT1. This modulation augments the suppression of p53 by SIRT1 while simultaneously increasing mitochondrial biogenesis through PGC-1α, which, in turn, promotes the survival and proliferation of stem cells. This figure was partly created with BioRender.com.

Figure 3

(A). The dysfunction of SIRT2 and SIRT3 in aged HSCs finally leads to HSC vulnerability. In aging HSCs, the activity of SIRT2 is decreased, resulting in an increase in NLRP3 inflammasome activity. In turn, the decrease in SIRT3 activity results in damage to HSCs due to ROS accumulation. (B). The main effects of SIRT4 in SC aging. SIRT4 dysfunction can affect the cellular functions outlined above. (C). SIRT5 upregulation mediated by CXCR4 via JAK2 can rescue normal mitochondrial function in ESCs. (D). SIRT6-mediated epigenetic regulatory functions in SCs. TET1/2 inhibition via Oct4, Sox2, and Nanog may affect neuroectodermal differentiation. Inhibition of Wnt target molecules may regulate the self-renewal capacity of HSCs. Stimulation of NRF2 target molecules may enhance the stress resistance of MSCs. (E). SIRT7 deletion enhances the osteogenic differentiation of MSCs in bone marrow by elevating H3K18ac levels at the promoter of the OSX transcription factor and activating the Wnt/β-catenin signaling pathway. This figure was partly created with BioRender.com.

Figure 4

Schematic representation of the role of SIRT1 in autophagy. EP300-mediated acetylation of ATG5, -7, and 12 molecules causes the inhibition of autophagy. Conversely, SIRT1-mediated deacetylation of these molecules stimulates autophagy. Deacetylation of LC3-I promotes translocation to the cytoplasm and then, via ATG3, ATG7, and PE, the formation of LC3-II, stimulating the mechanism of autophagy. This figure was partly created with BioRender.com.

Figure 5

Schematic overview of several molecular cross-talk between SIRT1/2 and autophagy in CSCs. SIRT1 affects acetylated p53, which regulates the stem cell phenotype of CSCs. SIRT1 function is also affected by miR-34a, CPEB, and c-Myc. c-Myc may be stimulated by mTORC–AMBRA1 interaction via PP2A, thereby indirectly affecting SIRT1 and CSC function. Notch signaling regulates SIRT2 function, which may affect CSC function by inhibiting the deacetylation of ALDH1A1. However, SIRT2 also affects autophagy and may influence changes in the phenotype of CSCs mainly through the LC3–CD105 interaction. This figure was partly created with BioRender.com.