Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer

Abstract

Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis and cancer metastasis in different types of human cancers, including breast cancer. Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC) that deacetylates both histone and non-histone targets. The often-described ‘regulator of regulators’ is deeply implicated in apoptosis, gene regulation, genome maintenance, DNA repair, aging, and cancer development. However, despite the accumulated studies over the past decade, the role of SIRT1 in human breast cancer remains a subject of debate and controversy. The ambiguity surrounding the implications of SIRT1 in breast tumorigenesis stems from the discrepancy between studies, which have shown both tumor-suppressive and promoting functions of SIRT1. Furthermore, studies have shown that SIRT1 deficiency promotes or suppresses tumors in breast cancer, making it an attractive therapeutic target in cancer treatment. This review provides a comprehensive examination of the various implications of SIRT1 in breast cancer development and metastasis. We will also discuss the mechanisms underlying the conflicting roles of SIRT1, as well as its selective modulators, in breast carcinogenesis.

The Role of Nicotinamide in Cancer Chemoprevention and Therapy

“…In contrast, Tan et al connected SIRT1 overexpression with shorter survival in luminal cancers [147], while Wu et al linked it with cancer progression and dismal prognosis in both TNBCs and non-TNBCs [148]. In fact, evidence that supports both a tumor promoter and suppressor function of SIRT1 has been reported for TNBC and luminal breast cancer subtypes [142]. Concerning PARP1, its up-regulation has been reported in multiple cancers, while its inhibition has the capacity to suppress angiogenesis, metastasis, and tumor-induced inflammation [48].…”

“…Therefore, it is not easy to say if NAM inhibits or in fact stimulates SIRT1 in the long term and more preclinical research in this direction would be vital [38]. To make things more complicated, SIRT1 exhibits a dichotomous behavior and has been described as both tumor promoter and suppressor, while both SIRT1 up-regulation and down-regulation have been associated with cancer progression [45,[139][140][141][142]. Some studies have suggested that SIRT1 behavior is dependent on the oncogenic context [142].…”

“…To make things more complicated, SIRT1 exhibits a dichotomous behavior and has been described as both tumor promoter and suppressor, while both SIRT1 up-regulation and down-regulation have been associated with cancer progression [45,[139][140][141][142]. Some studies have suggested that SIRT1 behavior is dependent on the oncogenic context [142]. For instance, SIRT1 overexpression has been reported to be a poor prognostic factor in TNBCs [143,144] but a favorable one in the luminal A hormone-positive breast cancers [145,146].…”

2-Hydroxyglutarate in Cancer Cells

“…In several types of cancer, SIRT1 is elevated and may serve as a tumor promoter. In contrast, in certain situations, SIRT1 may act as tumor suppressor (137).…”

SIRT6 is a DNA Double-Strand Break Sensor

“…Moreover, we tested LacR-SIRT1, SIRT2 and SIRT7 initiation capacity in the tethering assay since all these Sirtuins have the ability to localize to the nucleus and have been associated with DNA repair (Jeong et al, 2007;Li et al, 2016;Paredes and Chua, 2016;Rifaï et al, 2018;Vazquez et al, 2016Vazquez et al, , 2017Zhang et al, 2016). Remarkably, SIRT2 and SIRT7 could initiate the DDR, but SIRT1 could not (see note in methods) ( Fig.…”