ArticleScience signaling2014
MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer.
Article in Science signaling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers, 1 of them a synthesis that pooled it.
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Who cites it
63 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.
- Progress in epigenetic research of breast cancer: a bibliometric analysis since the 2000s.Frontiers in oncology · 2025Pooled it
- Long-lived mammals contain more phosphorylation sites in the SIRT6 C-terminus that enhance PARP1 interaction and resistance to oxidative stress.GeroScience · 2026Article
- PARP1 suppression by α7 nAChR activation attenuated α-synuclein-induced neurotoxicity in Parkinson's disease.Protein & cell · 2026Article
- Centenarian SIRT6 variants elevate SIRT6 protein and enhance cellular senescence resistance.Research square · 2026Article
- Long-lived mammals contain more phosphorylation sites in the SIRT6 C-terminus that enhance PARP1 interaction and resistance to oxidative stress.bioRxiv : the preprint server for biology · 2026Article
- SIRT6 in Cancer: Mechanistic Insights into Its Dual Roles in Cancer Biology and Implications for Precision Therapeutic Development.Biomolecules · 2025Review
- PKCδ Regulates DNA Damage and Cell Death through a SIRT6/Nrf2-dependent Antioxidant Response.Molecular cancer research : MCR · 2025Article
- Computational identification of potential natural terpenoid inhibitors of MDM2 for breast cancer therapy: molecular docking, molecular dynamics simulation, and ADMET analysis.Frontiers in chemistry · 2025Article
- SIRT6 Inhibits Anoikis of Colorectal Cancer Cells by Down-Regulating NDRG1.International journal of molecular sciences · 2024Article
- PKCδ Regulates Chromatin Remodeling and DNA Repair through SIRT6.Molecular cancer research : MCR · 2024Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- Targeting sirtuins for cancer therapy: epigenetics modifications and beyond.Theranostics · 2024Review
- SIRT6 promotes metastasis and relapse in HER2-positive breast cancer.Scientific reports · 2023Article
- Smooth muscle liver kinase B1 inhibits foam cell formation and atherosclerosis via direct phosphorylation and activation of SIRT6.Cell death & disease · 2023Article
- SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex.Nucleic acids research · 2023Article
- SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases.Aging and disease · 2022Review
- Review
- The prognostic implications of SIRTs expression in breast cancer: a systematic review and meta-analysis.Discover oncology · 2022Article
- The phosphorylation to acetylation/methylation cascade in transcriptional regulation: how kinases regulate transcriptional activities of DNA/histone-modifying enzymes.Cell & bioscience · 2022Review
- SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription.Cell death discovery · 2022Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Sirtuin 6 (SIRT6) is associated with longevity and is also a tumor suppressor. Identification of molecular regulators of SIRT6 might enable its activation therapeutically in cancer patients. In various breast cancer cell lines, we found that SIRT6 was phosphorylated at Ser(338) by the kinase AKT1, which induced the interaction and ubiquitination of SIRT6 by MDM2, targeting SIRT6 for protease-dependent degradation. The survival of breast cancer patients positively correlated with the abundance of SIRT6 and inversely correlated with the phosphorylation of SIRT6 at Ser(338). In a panel of breast tumor biopsies, SIRT6 abundance inversely correlated with the abundance of phosphorylated AKT. Inhibiting AKT or preventing SIRT6 phosphorylation by mutating Ser(338) prevented the degradation of SIRT6 mediated by MDM2, suppressed the proliferation of breast cancer cells in culture, and inhibited the growth of breast tumor xenografts in mice. Overexpressing MDM2 decreased the abundance of SIRT6 in cells, whereas overexpressing an E3 ligase-deficient MDM2 or knocking down endogenous MDM2 increased SIRT6 abundance. Trastuzumab (known as Herceptin) is a drug that targets a specific receptor common in some breast cancers, and knocking down SIRT6 increased the survival of a breast cancer cell exposed to trastuzumab. Overexpression of a nonphosphorylatable SIRT6 mutant increased trastuzumab sensitivity in a resistant breast cancer cell line. Thus, stabilizing SIRT6 may be a clinical strategy for overcoming trastuzumab resistance in breast cancer patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.