IDENTIFYING REGULATORS OF TIP60

Abstract

Metastasis remains the leading cause of breast cancer death worldwide. Recent studies have implicated the tumor suppressor Tat-interactive protein 60kDa (TIP60) in suppressing breast cancer metastasis. Using a siRNA screen to search for regulators of TIP60, the E3 ligase Thyroid hormone receptor interactor 12 (TRIP12) emerged as the most potent regulator of the level of TIP60. Interestingly, contrary to the degradation role of a ligase, TRIP12 depletion decreases TIP60 protein level indicating that TRIP12 positively regulates TIP60. The regulation is independent of TRIP12's ligase activity but requires the N-terminal portion containing the Armadillo domain (TRIP12 F4 1-749). Similar to TIP60’s metastasis suppressive function, TRIP12 represses cellular migration and correlates with lower metastasis occurrence in breast cancer patient datasets. In addition, expressing TRIP12 F4 1-749 portion which increases TIP60, attenuates metastasis in vivo. This study reveals a previously unknown role of TRIP12 in inhibition of breast cancer metastasis.