Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells

Abstract

EglN prolyl hydroxylases, a family of oxygen-sensing enzymes, hydroxylate distinct proteins to modulate diverse physiopathological signals. Aberrant regulations of EglNs result in multiple human diseases, including cancer. Different from EglN1 which function largely depends on the role of hypoxia-induce factor alpha (HIFα) in tumors, the functional significance and the upstream regulatory mechanisms of EglN2, especially in prostate cancer setting, remain largely unclear. Here, we demonstrated that dysregulation of EglN2 facilitated prostate cancer growth both in cells and in vivo. Notably, EglN2 was identified highly expressed in human prostate cancer tissues. Mechanically, Cullin 3-based E3 ubiquitin ligase SPOP, a well-characterized tumor suppressor in prostate cancer, could recognize and destruct EglN2. Meanwhile, androgen receptor (AR), playing a pivotal role in progression and development of prostate cancer, could transcriptionally up-regulate EglN2. Pathologically, SPOP loss-of-function mutations or AR amplification, frequently occurring in prostate cancers, could significantly accumulate EglN2 abundance. Therefore, our study not only underlines an oncogenic role of EglN2 in prostate cancer, but also highlights SPOP as a tumor suppressor to down-regulate EglN2 in prostate cancer.

SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association

“…[25][26][27] Recently, it was demonstrated that SPOP plays a tumor suppressive role in prostate and endometrial cancers and a tumor-promoting role in kidney cancer. [28][29][30][31] In this study, we report that SPOP participates in TLR-mediated signaling. We identified SPOP as a MyD88-associated protein with yeast two-hybrid technology.…”

The PHD1 oxygen sensor in health and disease

“…Also, PHD1 has been recently demonstrated to be targeted for degradation by an E3 ubiquitin ligase called speckle‐type POZ protein (SPOP), which is commonly mutated in prostate cancer (Zhang et al . ). In SPOP‐deficient prostate cancer cells, knockdown of PHD1 was sufficient to dampen increased cell colony formation introduced by loss of SPOP, thus implying an oncogenic role of PHD1 in that setting (Zhang et al .…”

“…In SPOP‐deficient prostate cancer cells, knockdown of PHD1 was sufficient to dampen increased cell colony formation introduced by loss of SPOP, thus implying an oncogenic role of PHD1 in that setting (Zhang et al . ). In addition, FBW7, another E3 ubiquitin ligase, negatively regulates PHD1 protein expression in an in vitro model of triple receptor‐negative breast cancer (Takada et al .…”

“…; Zhang et al . ). It has been shown that loss of PHD1 in breast cancer cells decreases proliferation via the induction of cyclin D1 (Zhang et al .…”

The emerging role of SPOP protein in tumorigenesis and cancer therapy

“…SPOP suppresses tumorigenesis and progression via regulation of cell growth, apoptosis, migration, invasion and drug resistance by targeting its downstream substrates in several types of human malignancies, including prostate, lung, gastric, liver, colon and endometrial cancers SPOP mutations and downregulation were detected in human PrCa tissues, and these mutations were also tightly correlated with a worse prognosis in patients with PrCa [61]. More importantly, extensive biochemical evidence has further indicated that SPOP functions as a tumor suppressor by promoting the degradation of oncogenic substrates in PrCa, including SRC3 [62], AR [63], TRIM24 [64], c-Myc [65], DEK [66], SENP7 [67], EglN2 [68], ATF2 [69], Cdc20 [70], ERG [71,81], BRD4 [72][73][74], PD-L1 [75] and cyclin E1 [76]. Due to the many publications and space limitations, we will not describe the tumor suppressive role that SPOP plays by promoting the ubiquitination and degradation of its substrates in PrCa in detail.…”