APC/C CDH1 ubiquitinates STAT3 in mitosis

STAT3, a transcription factor is classified as an oncogene (Bromberg et al., 1999). STAT3 undergoes over 80 posttranslational modifications, which include phosphorylation, acetylation, palmitoylation, methylation, and ubiquitination (Diallo and Herrera, 2021). Among these PTMs, phosphorylation on Tyr705 and Ser727 plays a key role in activating STAT3 in cancers (Huynh et al., 2019, Yu et al., 2009). STAT3 is considered an attractive therapeutic target, as aberrantly activated STAT3 can drive tumor growth in cancers. But, small molecule-based STAT3 inhibitors were unsuccessful in clinical trials, as inhibitors could not inhibit the multiple functions of STAT3 (Beebe et al., 2018). Further, STAT3 inhibitors also trigger a feedback pathway that mediates drug resistance (Zhao et al., 2016, Lee et al., 2014). To overcome drug resistance to STAT3 inhibitors, STAT3-specific degraders were recently identified. STAT3 degraders ubiquitinate STAT3, leading to growth inhibition in invitro and tumor regression in mice (Bai et al., 2019, Zhou et al., 2021). These findings suggest that triggering STAT3 degradation in cancers is a better strategy than STAT3 inhibition (Heppler and Frank, 2019, Dong et al., 2021). However, not much is known about the identity of other E3-ligases that ubiquitinate STAT3 in cancers. Therefore, to design better therapies to degrade STAT3, we sought to identify E3-ligases that ubiquitinate STAT3 in cancer cells. To identify the E3-ligases that ubiquitinate STAT3, we determined cell cycle-dependent ubiquitination of STAT3 in HEK293T cells and examined the link between STAT3 dephosphorylation and ubiquitination.

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