SIRT1 and gynecological malignancies (Review)

Abstract

Sirtuin 1 (SIRT1), a member of the sirtuin protein family, is a nicotinamide adenine dinucleotide (NAD⁺)‑dependent type III histone deacetylase and mono‑ADP‑ribosyltransferase. SIRT1 can deacetylate histones (H1, H3, and H4) and non‑histone proteins, and it is widely involved in various physiological and pathological processes in the body, including metabolism, aging, transcription, DNA damage and repair, apoptosis, cell cycle regulation, inflammation and cancer. Research has shown that SIRT1 is involved in tumorigenesis, tumor metastasis and chemotherapy resistance, but it exerts opposing effects and plays different roles in different pathogenic processes. Recent studies have demonstrated that SIRT1 may be implicated in the pathogenesis, development, treatment and prognosis of tumors; however, its role in gynecological tumors remains elusive. The aim of the present review was to summarize the pathogenic roles of SIRT1 in cancer, and to provide what is, to the best of our knowledge, the first review of recent advances involving SIRT1 in cervical cancer, endometrial cancer (EC) and ovarian cancer (OC). In addition, the critical research gaps regarding SIRT1, particularly its potential involvement in the concurrence of EC and cervical cancer and its antagonistic effect against poly(ADP‑ribose) polymerase inhibitors in OC, were highlighted.

Keywords: sirtuin 1; cervical cancer; endometrial cancer; ovarian cancer; poly(ADP‑ribose) polymerase inhibitors.

Figure 1.

Mechanism of PARPi in the treatment of ovarian cancer and the possible role of SIRT1. Synthetic lethality is the principle of PARPi; i.e., PARPi cause SSB repair defects leading to DSBs. When HRD coexists, a large number of DSBs cannot be repaired or are erroneously repaired, which eventually leads to cancer cell death. (A) SIRT1 interacts with PARP. SIRT1 reduces the level and function of PARP protein through transcription, post-translational modification (deacetylation) and competition for substrates, which may affect the therapeutic effect of PARPi. (B) SIRT1 promotes homologous recombination repair. SIRT1 increases the activity of NBS1, ATM and H2AX through deacetylation and promotes HR. Furthermore, it promotes cell cycle arrest and inhibits apoptosis, which promotes cell survival. When BRCA1 is mutated, HR repair defects may be compensated to some extent by increasing the expression of SIRT1. These findings indicate that SIRT1 may affect the therapeutic efficacy of PARPi. PARPi, poly(ADP-ribose) polymerase inhibitors; SSBs, single-strand breaks; DSBs, double-strand breaks; HRD, homologous recombination deficiency; NAD⁺, nicotinamide adenine dinucleotide; XRCC1, X-ray repair complementing defective repair in Chinese hamster cells 1; H2AX, histone H2AX; POLB, DNA polymerase-β; ATR, ATR serine/threonine kinase; ATM, ATM serine/threonine kinase; CHK1, checkpoint kinase 1; CHK2, checkpoint kinase 2; PALB2, partner and localizer of BRCA2.

Figure 2.

SIRT1 promotes persistent HPV infection and malignant transformation of cervical epithelial cells. SIRT1 promotes the onset of cervical cancer as follows: i) As a component of the E1-E2-replicating complex, it participates in the DNA duplication of HPV; ii) HPV infection causes host DNA damage and increases SIRT1 expression, which activates the DNA damage repair process (particularly HR). As a result, high fidelity of HPV DNA replication is ensured; iii) SIRT1 inhibits the apoptosis of infected epithelial cells; iv) SIRT1 decreases the transcription of inflammation-related factors, such as AIM2 and ILs, thereby helping infected cells escape the innate antiviral immunity. HPV, human papillomavirus; AIM2, absent in melanoma 2; IL, interleukin; TGFR, transforming growth factor receptor; NF-κB, nuclear factor κB; RB, retinoblastoma transcriptional corepressor.