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 physiological and pathological conditions, and provided insights in understanding the relationship between SPOP mutations and the development of endometrial cancer.
Highlights
speckle-type POZ protein (SPOP) is an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex
We demonstrated that SPOP forms a functional CUL3-SPOP-RBX1 E3 ubiquitin ligase complex which targets Estrogen receptor-α (ERα) for ubiquitination and proteasomal degradation in endometrial cancer cells
Because ERα is the most extensively studied biomarker and the best predictor for response to endocrine therapy in patients with endometrial cancer, we explored the possibility that SPOP regulates ERα protein stability via a similar mechanism as that of androgen receptor (AR) stability
Summary
SPOP is an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex. It selectively recruits substrates via its. N-terminal MATH domain, whereas its BTB domain mediates dimerization and interaction with CUL3.8 SPOP has been linked to the ubiquitination of several substrates in both Drosophila and human cells, including the steroid receptor coactivator SRC-3, death domain-associated protein Daxx, the phosphatase Puc, the transcriptional regulator Ci/Gli, and several others.. Estrogen receptor-α (ERα), encoded by ESR1 gene, is a nuclear transcriptional factor that mediates estrogenstimulated cell proliferation in hormone-responsive cancers, such as breast, endometrial and ovarian cancers.. We demonstrated that SPOP forms a functional CUL3-SPOP-RBX1 E3 ubiquitin ligase complex which targets ERα for ubiquitination and proteasomal degradation in endometrial cancer cells. This effect is abrogated by the endometrial cancer-associated SPOP mutations. Our results provide a functional insight into the molecular mechanism of endometrial cancer pathway involved with SPOP mutations
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