Destruction of a microtubule-bound MYC reservoir during mitosis contributes to vincristines anti-cancer activity.

Tightly regulated activity of the transcription factor MYC is essential for orderly cell proliferation. Upon deregulation, MYC elicits and promotes cancer progression. Proteasomal degradation is an essential element of MYC regulation, initiated by phosphorylation at Serine62 (Ser62) of the MB1 region. Here we found that Ser62 phosphorylation peaks in mitosis, but that a fraction of non-phosphorylated MYC binds to the microtubules of the mitotic spindle. Consequently, the microtubule-destabilizing drug vincristine decreases wildtype MYC stability, while phosphorylation-deficient MYC is more stable, contributing to vincristine resistance and induction of polyploidy. PI3K inhibition attenuates post-mitotic MYC formation and augments the cytotoxic effect of vincristine. Implications: The spindle’s function as a docking site for MYC during mitosis may constitute a window of specific vulnerability to be exploited for cancer treatment.