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.
Highlights
Intermittent oxygen deficiency in cancer microenvironment promotes prolonged inflammation, continuous neovascularization, and escalated drug resistance
We studied rhomboid family-1 (RHBDF1) expression levels in the tumor specimens of 67 patients with breast cancer who had completed a full protocol of neoadjuvant chemotherapy before surgical excision of the tumor
These findings indicate that elevated RHBDF1 expression in breast cancer is strongly correlated with facilitated disease progression, local recurrence, lymph node and distant metastasis, poor prognosis, and poor responses to chemotherapy
Summary
Intermittent oxygen deficiency in cancer microenvironment promotes prolonged inflammation, continuous neovascularization, and escalated drug resistance. The transcription factor hypoxia-inducible factor-1 (HIF1) predominantly regulates cellular responses to oxygen deficiency, including the expression of genes required for tissue oxygen delivery and energy metabolism in developmental, physiologic, and pathologic conditions such as ischemic cardiovascular disease, stroke, and cancer [1]. Authors' Affiliations: 1State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy and 2Tianjin Key Laboratory of Molecular Drug Research, Nankai University; 3Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer; 4Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; and 5Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
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