TY - JOUR
T1 - Endometrial cancer-associated mutants of SPOP are defective in regulating estrogen receptor-α protein turnover
AU - Zhang, P.
AU - Gao, K.
AU - Jin, X.
AU - Ma, J.
AU - Peng, J.
AU - Wumaier, R.
AU - Tang, Y.
AU - Zhang, Y.
AU - An, J.
AU - Yan, Q.
AU - Dong, Y.
AU - Huang, H.
AU - Yu, L.
AU - Wang, C.
N1 - Funding Information:
We thank Dr. Masatoshi Hagiwara for providing the HA-SPOP constructs. This work was supported by the National Natural Science Foundation of China (30872947 to PZ, 81472567 to LY, and 81171964 to CJ).
Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved.
PY - 2015
Y1 - 2015
N2 - Increasing amounts of evidence strongly suggests that dysregulation of ubiquitin-proteasome system is closely associated with cancer pathogenesis. Speckle-type POZ protein (SPOP) is an adapter protein of the CUL3-based E3 ubiquitin ligase complexes. It selectively recruits substrates for their ubiquitination and subsequent degradation. Recently, several exome-sequencing studies of endometrial cancer revealed high frequency somatic mutations in SPOP (5.7–10%). However, how SPOP mutations contribute to endometrial cancer remains unknown. Here, we identified estrogen receptor-α (ERα), a major endometrial cancer promoter, as a substrate for the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP specifically recognizes multiple Ser/Thr (S/T)-rich degrons located in the AF2 domain of ERα, and triggers ERα degradation via the ubiquitin-proteasome pathway. SPOP depletion by siRNAs promotes endometrial cells growth. Strikingly, endometrial cancer-associated mutants of SPOP are defective in regulating ERα degradation and ubiquitination. Furthermore, we found that SPOP participates in estrogen-induced ERα degradation and transactivation. Our study revealed novel molecular mechanisms underlying the regulation of ERα protein homeostasis in physiological and pathological conditions, and provided insights in understanding the relationship between SPOP mutations and the development of endometrial cancer.
AB - Increasing amounts of evidence strongly suggests that dysregulation of ubiquitin-proteasome system is closely associated with cancer pathogenesis. Speckle-type POZ protein (SPOP) is an adapter protein of the CUL3-based E3 ubiquitin ligase complexes. It selectively recruits substrates for their ubiquitination and subsequent degradation. Recently, several exome-sequencing studies of endometrial cancer revealed high frequency somatic mutations in SPOP (5.7–10%). However, how SPOP mutations contribute to endometrial cancer remains unknown. Here, we identified estrogen receptor-α (ERα), a major endometrial cancer promoter, as a substrate for the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP specifically recognizes multiple Ser/Thr (S/T)-rich degrons located in the AF2 domain of ERα, and triggers ERα degradation via the ubiquitin-proteasome pathway. SPOP depletion by siRNAs promotes endometrial cells growth. Strikingly, endometrial cancer-associated mutants of SPOP are defective in regulating ERα degradation and ubiquitination. Furthermore, we found that SPOP participates in estrogen-induced ERα degradation and transactivation. Our study revealed novel molecular mechanisms underlying the regulation of ERα protein homeostasis in physiological and pathological conditions, and provided insights in understanding the relationship between SPOP mutations and the development of endometrial cancer.
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U2 - 10.1038/CDDIS.2015.47
DO - 10.1038/CDDIS.2015.47
M3 - Article
C2 - 25766326
AN - SCOPUS:84965085978
SN - 2041-4889
VL - 6
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 3
M1 - e1687
ER -