SIRT1 knockdown up-regulates p53 and p21/Cip1 expression in renal adenocarcinoma cells but not in normal renal-derived cells in a deacetylase-independent manner

• Published in: Journal of toxicological sciences 2018, Vol.43(12), pp.711-715
• Main Authors: Fujino, Tomofumi, Yokokawa, Rina, Oshima, Toshiyuki, Hayakawa, Makio
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Carcinoma, Renal Cell - metabolism; Carcinoma-specific cytotoxicity; Cell Line; Cell proliferation; Cyclin-dependent kinase; Cyclin-dependent kinase inhibitor; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinases; Deacetylase-independent; Deacetylation; Gene expression; Gene Knockdown Techniques; GTP-binding protein; Humans; Inhibitors; Kidney - metabolism; Kidneys; Kinases; NAD; p53 Protein; Post-transcription; Proteins; RNA, Messenger - metabolism; SIRT1; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Up-Regulation
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.43.711

SIRT1, an NAD+-dependent deacetylase, causes deacetylation and down-regulation of its target p53. Given that p53 is an upstream regulator of the transcription of the cyclin-dependent kinase inhibitor p21/Cip1, SIRT1 is hypothesized to play a stimulatory role in carcinoma cell proliferation. We previously reported that down-regulation of SIRT1 caused the increase in p21/Cip1 in a post-transcriptional manner, suggesting that p53 is not involved in the p21/Cip1 increase and raising the question whether SIRT1 exhibits the activity other than deacetylase. In the present study, we examined whether SIRT1 down-regulation and the inhibitor for SIRT1 deacetylase activity affects p21/Cip1 and p53 expression in renal adenocarcinoma cells and normal renal cells. SIRT1 knockdown caused an increase in p53 and p21/Cip1 protein levels in renal adenocarcinoma ACHN cells but not normal renal-derived HK-2 cells. The increase in p53 in ACHN cells is unlikely to contribute to the upregulation of p21/Cip1 expression, given that SIRT1 knockdown did not increase p21/Cip1 mRNA levels in these cells. In contrast to the SIRT1-knock down assay, SIRT1 deacetylase inhibitor did not affect p53 or p21/Cip1 protein levels in ACHN cells. Therefore, SIRT1-knockdown likely stimulates p53 and p21/Cip1 protein expression in a deacetylase-independent manner.