TY - JOUR
T1 - Acetylation-dependent regulation of Skp2 function
AU - Inuzuka, Hiroyuki
AU - Gao, Daming
AU - Finley, Lydia W.S.
AU - Yang, Wen
AU - Wan, Lixin
AU - Fukushima, Hidefumi
AU - Chin, Y. Rebecca
AU - Zhai, Bo
AU - Shaik, Shavali
AU - Lau, Alan W.
AU - Wang, Zhiwei
AU - Gygi, Steven P.
AU - Nakayama, Keiko
AU - Teruya-Feldstein, Julie
AU - Toker, Alex
AU - Haigis, Marcia C.
AU - Pandolfi, Pier Paolo
AU - Wei, Wenyi
N1 - Funding Information:
We thank Lewis Cantley, Pengda Liu, and Qing Zhang for critical reading of the manuscript; Christoph Geisen, Yasuyujki Fujita, and Hui-Kuan Lin for providing reagents; and members of the Wei, Haigis, Pandolfi, and Toker labs for useful discussions. W.W. is an MLSC New Investigator and an American Cancer Society Research Scholar (W.W., RSG-12-096). This work was supported in part by the Susan G. Komen Breast Cancer Foundation (Y.R.C., 0706963), the Department of Defense Prostate Cancer Research Program (W.W., PC080377), and by grants from the National Institutes of Health (W.W., GM089763, GM094777; A.T., CA122099; H.I., AG041218).
PY - 2012/7/6
Y1 - 2012/7/6
N2 - Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers. Here, we report that Skp2 is acetylated by p300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase. Inactivation of SIRT3 leads to elevated Skp2 acetylation, which leads to increased Skp2 stability through impairment of the Cdh1-mediated proteolysis pathway. As a result, Skp2 oncogenic function is increased, whereby cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo. Moreover, acetylation of Skp2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic Skp2 enhances cellular migration through ubiquitination and destruction of E-cadherin. Thus, our study identifies an acetylation-dependent regulatory mechanism governing Skp2 oncogenic function and provides insight into how cytoplasmic Skp2 controls cellular migration.
AB - Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers. Here, we report that Skp2 is acetylated by p300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase. Inactivation of SIRT3 leads to elevated Skp2 acetylation, which leads to increased Skp2 stability through impairment of the Cdh1-mediated proteolysis pathway. As a result, Skp2 oncogenic function is increased, whereby cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo. Moreover, acetylation of Skp2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic Skp2 enhances cellular migration through ubiquitination and destruction of E-cadherin. Thus, our study identifies an acetylation-dependent regulatory mechanism governing Skp2 oncogenic function and provides insight into how cytoplasmic Skp2 controls cellular migration.
UR - http://www.scopus.com/inward/record.url?scp=84863618431&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.05.038
DO - 10.1016/j.cell.2012.05.038
M3 - Article
C2 - 22770219
AN - SCOPUS:84863618431
SN - 0092-8674
VL - 150
SP - 179
EP - 193
JO - Cell
JF - Cell
IS - 1
ER -