title: Human rhomboid family-1 suppresses oxygen-independent degradation of hypoxia-inducible factor-1α in breast cancer.
abstract: Intermittent oxygen deficiency in cancers promotes prolonged inflammation, continuous angiogenesis, and increased drug resistance. Hypoxia-inducible factor-1 (HIF1) has a pivotal role in the regulation of cellular responses to oxygen deficiency. The α-subunit of HIF1 (HIF1α) is degraded in normoxia but stabilized in hypoxia. However, the molecular mechanism that controls oxygen-independent degradation of HIF1α has remained elusive. Human rhomboid family-1 (RHBDF1) is a member of a large family of nonprotease rhomboids whose function is basically unknown. We report here that RHBDF1 expression in breast cancer is highly elevated and is strongly correlated with escalated disease progression, metastasis, poor prognosis, and poor response to chemotherapy. We show that RHBDF1 interaction with the receptor of activated protein-C kinase-1 (RACK1) in breast cancer cells prevents RACK1-assisted, oxygen-independent HIF1α degradation. In addition, we show that the HIF1α-stabilizing activity of RHBDF1 diminishes when the phosphorylation of a tyrosine residue on the RHBDF1 molecule is inhibited. These findings are consistent with the view that RHBDF1 is a critical component of a molecular switch that regulates HIF1α stability in cancer cells in hypoxia and that RHBDF1 is of potential value as a new target for cancer treatment.
authors.affiliation: Authors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Authors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Authors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Zhi-Song
authors.initials: ZS
authors.lastname: Zhang
authors.affiliation: Authors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Shu
authors.affiliation: Authors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Authors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, China liluyuan@nankai.edu.cn fuli@tijmu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.affiliation: Authors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, ChinaAuthors' Affiliations: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University; Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, China liluyuan@nankai.edu.cn fuli@tijmu.edu.cn.
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D018450:Disease Progression; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D061986:MCF-7 Cells; D008565:Membrane Proteins; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; C081962:RHBDF1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D066246:ErbB Receptors; D019204:GTP-Binding Proteins; D010100:Oxygen