title: PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression.
abstract: 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 2 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 2 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.
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.|b National Center for Liver Cancer , Shanghai , China.
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.|b National Center for Liver Cancer , Shanghai , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.|b National Center for Liver Cancer , Shanghai , China.
authors.forename: An
authors.initials: A
authors.lastname: Xu
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.|b National Center for Liver Cancer , Shanghai , China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Ren
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Rongyang
authors.initials: R
authors.lastname: Dai
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Bibo
authors.initials: B
authors.lastname: Wang
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Qin
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Jiang
authors.affiliation: d Department of Nutrition and Endocrinology , Changhai Hospital , Shanghai , China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.
authors.forename: Gensheng
authors.initials: G
authors.lastname: Feng
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.|b National Center for Liver Cancer , Shanghai , China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: a International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital , Shanghai , China.|b National Center for Liver Cancer , Shanghai , China.|c State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7 / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D000076249:Heat Shock Transcription Factors / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7
keywords: ATG7; HSF1; PSMD10; autophagy; drug resistance; hepatocellular carcinoma; sorafenib