title: SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop.
abstract: We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.
  
  
  
  HCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed.
  
  
  
  We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α.
  
  
  
  Taken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Cui
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Alan Ka-Lun
authors.initials: AK
authors.lastname: Kai
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Daniel Wai-Hung
authors.initials: DW
authors.lastname: Ho
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong.
authors.forename: Eunice Yuen-Ting
authors.initials: EY
authors.lastname: Lau
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Yu-Man
authors.initials: YM
authors.lastname: Tsui
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Lo-Kong
authors.initials: LK
authors.lastname: Chan
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Tan-To
authors.initials: TT
authors.lastname: Cheung
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Kenneth Siu-Ho
authors.initials: KS
authors.lastname: Chok
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Albert C Y
authors.initials: ACY
authors.lastname: Chan
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Regina Cheuk-Lam
authors.initials: RC
authors.lastname: Lo
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Joyce Man-Fong
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong.
authors.forename: Terence Kin-Wah
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Irene Oi Lin
authors.initials: IOL
authors.lastname: Ng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025842:SUMO-1 Protein / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases
keywords: HEPATOCELLULAR CARCINOMA; MOLECULAR BIOLOGY; MOLECULAR PATHOLOGY; SIGNALING