title: Differential regulation of LncRNA-SARCC suppresses VHL-mutant RCC cell proliferation yet promotes VHL-normal RCC cell proliferation via modulating androgen receptor/HIF-2α/C-MYC axis under hypoxia.
abstract: It is well established that hypoxia contributes to tumor progression in a hypoxia inducible factor-2α (HIF-2α)-dependent manner in renal cell carcinoma (RCC), yet the role of long noncoding RNAs (LncRNAs) involved in hypoxia-mediated RCC progression remains unclear. Here we demonstrate that LncRNA-SARCC (Suppressing Androgen Receptor in Renal Cell Carcinoma) is differentially regulated by hypoxia in a von Hippel-Lindau (VHL)-dependent manner both in RCC cell culture and clinical specimens. LncRNA-SARCC can suppress hypoxic cell cycle progression in the VHL-mutant RCC cells while derepress it in the VHL-restored RCC cells. Mechanism dissection reveals that LncRNA-SARCC can post-transcriptionally regulate androgen receptor (AR) by physically binding and destablizing AR protein to suppress AR/HIF-2α/C-MYC signals. In return, HIF-2α can transcriptionally regulate the LncRNA-SARCC expression via binding to hypoxia-responsive elements on the promoter of LncRNA-SARCC. The negative feedback modulation between LncRNA-SARCC/AR complex and HIF-2α signaling may then lead to differentially modulated RCC progression in a VHL-dependent manner. Together, these results may provide us a new therapeutic approach via targeting this newly identified signal from LncRNA-SARCC to AR-mediated HIF-2α/C-MYC signals against RCC progression.
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.|George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhai
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Lab of Nuclear Receptors and Cancer Research, School of Medicine, Nantong University, Nantong, Jiangsu, China.
authors.forename: M
authors.initials: M
authors.lastname: Jiang
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Gasiewicz
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.|Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan.
authors.forename: C
authors.initials: C
authors.lastname: Chang
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D011944:Receptors, Androgen; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C410798:AR protein, human; C489427:MYC protein, human; C000622227:long noncoding SARCC, human; C497446:VHL protein, human