Endometrial cancer-associated mutants of SPOP are defective in regulating estrogen receptor-α protein turnover.

Cell Death & Disease
Pingzhao ZhangC Wang

Abstract

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 ph...Continue Reading

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Citations

Feb 24, 2016·Journal of Nutrition and Metabolism·Daniel B. HoffmannStephan Sehmisch
Dec 23, 2015·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Jianfei Qi, Ze'ev A Ronai
May 21, 2016·Frontiers in Oncology·Hsin-Yi Chen, Ruey-Hwa Chen
May 14, 2016·Reproductive Sciences·Na LiuXueqing Liu
Mar 17, 2018·Biology of Reproduction·Lan HaiJohn P Lydon
May 26, 2016·The EMBO Journal·Melissa R MarzahnTanja Mittag
Sep 9, 2019·The FEBS Journal·Matthew J Cuneo, Tanja Mittag
Jan 7, 2020·Molecular Cancer·Yizuo SongXueqiong Zhu
Apr 8, 2021·Cell and Tissue Research·Cristina M Cummings, Jeffrey D Singer
Apr 17, 2021·Biochemical and Biophysical Research Communications·Jian WangXiaofeng Jin
Apr 29, 2021·Open Biology·Fatemeh AliabadiThomas J Webster
Jun 3, 2021·Archives of Insect Biochemistry and Physiology·Jiao LvZuoming Nie

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Methods Mentioned

BETA
exome-sequencing
ubiquitination
AR
co-immunoprecipitation
co-IP
transfection

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