SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells

Abstract

BCR-ABL transforms bone marrow progenitor cells and promotes genome instability, leading to development of chronic myelogenous leukemia (CML). The tyrosine kinase inhibitor imatinib effectively treats CML, but acquired resistance can develop due to BCR-ABL mutations. Mechanisms for acquisition of BCR-ABL mutations are not fully understood. Using a novel culture model of CML acquired resistance, we show that inhibition of SIRT1 deacetylase by small molecule inhibitors or gene knockdown blocks acquisition of BCR-ABL mutations and relapse of CML cells on tyrosine kinase inhibitors. SIRT1 knockdown also suppresses de novo genetic mutations of HPRT (hypoxanthine phosphoribosyl transferase) gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin. Although SIRT1 can enhance cellular DNA damage response, it alters functions of DNA repair machineries in CML cells and stimulates activity of error-prone DNA damage repair, in association with acquisition of genetic mutations. These results reveal a previously unrecognized role of SIRT1 for promoting mutation acquisition in cancer, and have implication for targeting SIRT1 to overcome CML drug resistance.

Emerging Roles of SIRT1 in Cancer Drug Resistance

“…The study by Wang et al 88 contrasts with our conventional thinking that increased DNA damage repair should lead to reduced mutations. This surprise may be an unusual outcome of the aberrant DNA repair process in cancer cells under stress in which repair may be guided more towards fixing fatal DNA damage, for example, truncation of BCR-ABL, to avoid cell death, whereas it occurs with compromised repair fidelity, 89,90 leading to nonfatal point mutations.…”

“…80,92 More studies are needed to further uncover the precise molecular mechanisms of SIRT1 in therapeutic and endogenous stress signaling and DNA repair. Nonetheless, the study by Wang et al 88 provides the first evidence that acquired resistance through mutation acquisition can be regulated by SIRT1. Acquired resistance is a widespread phenomenon in targeted therapy, and it would be interesting to determine in the future if acquired resistance through acquisition of mutations in other types of cancer can be regulated and how SIRT1 may play a role in those settings.…”

“…In contrast to DNA damage induction by camptothecin, imatinib does not act through enhancing DNA damage, 81 and suppression of mutation acquisition by SIRT1 inhibition does not require increased cell killing. 88 Wang et al 88 showed that SIRT1 promotes mutation acquisition in association with its ability to enhance error-prone NHEJ DNA damage repair through deacetylating Ku70. Inhibition of Ku70 or HR repair factors NBS and RAD51 all suppresses BCR-ABL mutations, with the latter apparently impacting NHEJ activity.…”

“…Interestingly, most, if not all, BCR-ABL mutations are acquired de novo in this model, suggesting a previously underestimated route of mutation acquisition that may contribute to the faster relapse of cancer patients under therapeutic stress. 87 By using the KCL-22 cell model, Wang et al 88 showed that SIRT1 is a critical factor for promoting the acquisition of genetic mutations of BCR-ABL for CML resistance. SIRT1 gene knockdown or inhibition by small molecule inhibitors blocks the acquisition of BCR-ABL mutations in CML cells and prevents CML cell relapse from TKIs.…”

Sirtuins, Tissue Maintenance, and Tumorigenesis

“…SIRT1 deacetylates many components of the DNA damage response and DNA repair pathways, including Ku70, Nijmegen breakage syndrome protein (NBS1), and Werner syndrome protein (WRN). 45,67,68 SIRT1 can enhance nonhomologous end joining (NHEJ), an efficient yet errorprone DNA repair mechanism. 64,68,69 While SIRT1 may help CML LSCs repair DNA damage and escape apoptosis, it may also facilitate the accumulation of new mutations and promote disease evolution and drug resistance.…”