PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression.
Although autophagy is most critical for survival of cancer cells, especially in fast-growing tumors, the mechanism remains to be fully characterized. Herein we report that PSMD10/gankyrin promotes autophagy in hepatocellular carcinoma (HCC) in response to starvation or stress through 2Â complementary routes. PSMD10 was physically associated with ATG7 in the cytoplasm, ... and this association was enhanced by initial nutrient deprivation. Subsequently, PSMD10 translocated into the nucleus and bound cooperatively with nuclear HSF1 (heat shock transcription factor 1) onto the ATG7 promoter, upregulated ATG7 expression in the advanced stage of starvation. Intriguingly, the type of PSMD10-mediated autophagy was independent of the proteasome system, although PSMD10 has been believed to be an indispensable chaperone for assembly of the 26S proteasome. A significant correlation between PSMD10 expression and ATG7 levels was detected in human HCC biopsies, and the combination of these 2Â parameters is a powerful predictor of poor prognosis. The median survival of sorafenib-treated HCC patients with high expression of PSMD10 was much shorter than those with low expression of PSMD10. Furthermore, PSMD10 augmented autophagic flux to resist sorafenib or conventional chemotherapy, and inhibition of autophagy suppressed PSMD10-mediated resistance. We conclude that these results present a novel mechanism involving modulation of ATG7 by PSMD10 in sustaining autophagy, promoting HCC cell survival against starvation or chemotherapy. Targeting of PSMD10 might therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to drugs.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Autophagy, Autophagy-Related Protein 7, Carcinoma, Hepatocellular, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Cell Survival, Cytoplasm, Disease Progression, Heat Shock Transcription Factors, Humans, Liver Neoplasms, Male, Mice, Mice, Nude, Mice, Transgenic, Neoplasm Transplantation, Prognosis, Proteasome Endopeptidase Complex, Protein Binding, Proto-Oncogene Proteins, Transcriptional Activation
Active Transport, Cell Nucleus, Animals, Autophagy, Autophagy-Related Protein 7, Carcinoma, Hepatocellular, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Cell Survival, Cytoplasm, Disease Progression, Heat Shock Transcription Factors, Humans, Liver Neoplasms, Male, Mice, Mice, Nude, Mice, Transgenic, Neoplasm Transplantation, Prognosis, Proteasome Endopeptidase Complex, Protein Binding, Proto-Oncogene Proteins, Transcriptional Activation
Autophagy
Date: Dec. 02, 2015
PubMed ID: 25905985
View in: Pubmed Google Scholar
Download Curated Data For This Publication
212656
Switch View:
- Interactions 9