SIRT6 Suppresses Cancer Stem-like Capacity in Tumors with PI3K Activation Independently of Its Deacetylase Activity.
Authors | |
Abstract | Cancer stem cells (CSCs) have high tumorigenic capacity. Here, we show that stem-like traits of specific human cancer cells are reduced by overexpression of the histone deacetylase sirtuin 6 (SIRT6). SIRT6-sensitive cancer cells bear mutations that activate phosphatidylinositol-3-kinase (PI3K) signaling, and overexpression of SIRT6 reduces growth, progression, and grade of breast cancer in a mouse model with PI3K activation. Tumor metabolomic and transcriptomic analyses reveal that SIRT6 overexpression dampens PI3K signaling and stem-like characteristics and causes metabolic rearrangements in this cancer model. Ablation of a PI3K activating mutation in otherwise isogenic cancer cells is sufficient to convert SIRT6-sensitive into SIRT6-insensitive cells. SIRT6 overexpression suppresses PI3K signaling at the transcriptional level and antagonizes tumor sphere formation independent of its histone deacetylase activity. Our data identify SIRT6 as a putative molecular target that hinders stemness of tumors with PI3K activation. |
Year of Publication | 2017
|
Journal | Cell Rep
|
Volume | 18
|
Issue | 8
|
Pages | 1858-1868
|
Date Published | 2017 Feb 21
|
ISSN | 2211-1247
|
DOI | 10.1016/j.celrep.2017.01.065
|
PubMed ID | 28228253
|
PubMed Central ID | PMC5329120
|
Links | |
Grant list | R01 LM010235 / LM / NLM NIH HHS / United States
|