Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer

Abstract

Prostate cancer (PCa) is a major lethal malignancy in men, but the molecular events and their interplay underlying prostate carcinogenesis remain poorly understood. Epigenetic events and the upregulation of polycomb group silencing proteins including Bmi1 have been described to occur during PCa progression. Here, we found that conditional overexpression of Bmi1 in mice induced prostatic intraepithelial neoplasia, and elicited invasive adenocarcinoma when combined with PTEN haploinsufficiency. In addition, Bmi1 and the PI3K/Akt pathway were coactivated in a substantial fraction of human high-grade tumors. We found that Akt mediated Bmi1 phosphorylation, enhancing its oncogenic potential in an Ink4a/Arf-independent manner. This process also modulated the DNA damage response and affected genomic stability. Together, our findings demonstrate the etiological role of Bmi1 in PCa, unravel an oncogenic collaboration between Bmi1 and the PI3K/Akt pathway, and provide mechanistic insights into the modulation of Bmi1 function by phosphorylation during prostate carcinogenesis.

BMI1–RING1B is an autoinhibited RING E3 ubiquitin ligase

“…Taken together, these data support cooperation between E3 recognition of both ubiquitin and nucleosome in promoting H2A ubiquitination. It remains to be determined in detail how other PRC1 complex components, or regulatory mechanisms such as activating phosphorylation of PCGF proteins 53,54 or inactivating phosphorylation of RING1B within PRC1.5 (ref. 55), influence E3 ligase activity of canonical and non-canonical PRC1.…”

USP3 counteracts RNF168 via deubiquitinating H2A and γH2AX at lysine 13 and 15

“…23 The PRC1 component BMI1 is found to be recruited to damage sites and contributes to K119 ubiquitination of H2A and DNA break repair. 23,24 Little is known about H2A and γH2AX deubiquitination, a reverse process which removes Ub moiety from target protein.…”

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

“…Previous reports indicate that kinases can phosphorylate E3 ligase to negatively or positively regulate an enzymatic activity. [29][30][31][32] Interestingly, our present data provide a novel regulatory mechanism of CHIP by demonstrating that Cdk5-mediated phosphorylation does not decrease its E3 ligase activity. Rather, Cdk5-mediated CHIP phosphorylation causes disruption of the interaction between CHIP and its substrate, tAIF.…”

“…Our data can be interpreted as a consequence of either loss of CHIP's E3 ligase activity or other unknown mechanisms. Based on the previous evidence supporting that the phosphorylation of E3 ligases by kinases regulates its ligase activity, [29][30][31][32] therefore, we first attempted to check whether Cdk5-mediated phosphorylation affects CHIP's E3 ligase activity. Auto-ubiquitination assay was conducted to measure E3 ligase activity (Figures 4a and b).…”