Abstract 120P
Background
Protein phosphatase Mg2+/Mn2+–dependent 1D (PPM1D) is a central negative regulator of the DNA damage response that is frequently overexpressed in many solid cancers. We investigate its role in driving hepatocellular carcinoma (HCC) progression and therapeutic implications.
Methods
In vitro and in vivo experiments were constructed to validate the function of PPM1D on HCC behavior. Immunoprecipitation (IP) and mass spectrometry were used to find the interactor of PPM1D. Co-IP, GST-pull down and DUOlink PLA were used to verify the interaction. ChIP-PCR and luciferase assays were used to confirm the binding of transcription factor on PPM1D promoter.
Results
PPM1D was overexpressed in HCC samples and correlated with inferior patient prognosis. The oncogenic role of PPM1D in HCC cell lines was confirmed in vitro and in vivo. Mechanistically, PPM1D directly interacts with PKM2 in the cytoplasm of HCC cells, inhibits its proteasomal degradation, thus promoting glycolysis and maintaining mitochondrial homeostasis. Effector T cells induced by anti-PD1 therapy upregulates PPM1D expression through an TNFα-NFκB-dependent pathway. Blocking PPM1D potentiates anti-PD-1 treatment in HCC mouse models without causing additional cytotoxicity.
Conclusions
Our study identifies PPM1D as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Liang Zhang.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.