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

Abstract

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 PTENR173H and PTENR173C 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.

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Fig. 1: HOIP depletion suppresses PCa cell progression.
Fig. 2: HOIP contributes to the activation of AKT signaling pathway in a PTEN-dependent manner.
Fig. 3: LUBAC binds to PTEN.
Fig. 4: PTEN harbors M1-Ubi mediated by LUBAC.
Fig. 5: PTEN M1-Ubi suppresses its phosphatase activity.
Fig. 6: Cancer-associated PTEN mutants with high M1-Ubi interfere with PTEN function in the regulation of AKT signaling.
Fig. 7: Clinical impact of HOIP expression on PCa progression.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

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Funding

This work was supported by grants from China’s National Key R&D Programmes (NKP) (No. 2019YFE0110600), the National Natural Science Foundation of China (81630075, 82103082, 81721004, 81902866, 82002712, 81972585) and Shanghai Science and Technology Commission (20JC1410100).

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J.Y., Y.G., and H.Z. conceived and designed the study. Y.G., J.H., H.Z., and R.C. performed most of the experiments. L.L., X.L., C.H., Z.Q., Z.Z., Y.W., J.H., and X.Z. helped with experiments and provided technical support. J.H., X.Z., J.Z., and G.C. offered some constructive suggestions. J.Y., Y.G., J.H., and H.Z. analyzed the data. J.Y. and Y.G. wrote the paper.

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Correspondence to Jianxiu Yu.

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Guo, Y., He, J., Zhang, H. et al. Linear ubiquitination of PTEN impairs its function to promote prostate cancer progression. Oncogene 41, 4877–4892 (2022). https://doi.org/10.1038/s41388-022-02485-6

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