Linear ubiquitination of PTEN impairs its function to promote prostate cancer progression.

PTEN is frequently mutated in human cancers, which leads to the excessive activation of PI3K/AKT signaling and thus promotes tumorigenesis and drug resistance. Met¹-linked ubiquitination (M1-Ubi) is also involved in cancer progression, but the mechanism is poorly defined. Here we find that HOIP, one important component of linear ubiquitin chain assembly complex (LUBAC), promotes prostate cancer (PCa) progression by enhancing AKT signaling in a PTEN-dependent manner. Mechanistically, PTEN is modified by M1-Ubi at two sites K144 and K197, which significantly inhibits PTEN phosphatase activity and thus accelerates PCa progression. More importantly, we identify that the high-frequency mutants PTEN^R173H and PTEN^R173C in PCa patients showed the enhanced level of M1-Ubi, which impairs PTEN function in inhibition of AKT phosphorylation and cell growth. We also find that HOIP depletion sensitizes PCa cells to therapeutic agents BKM120 and Enzalutamide. Furthermore, the clinical data analyses confirm that HOIP is upregulated and positively correlated with AKT activation in PCa patient specimen, which may promote PCa progression and increase the risk of PCa biochemical relapse. Together, our study reveals a key role of PTEN M1-Ubi in regulation of AKT activation and PCa progression, which may propose a new strategy for PCa therapy.