A domain responsible for HIF-1alpha degradation by YC-1, a novel anticancer agent.
HIF-1alpha is believed to promote tumor growth and metastasis, and many efforts have been made to develop new anticancer agents based on HIF-1alpha inhibition. YC-1 is a widely used HIF-1alpha inhibitor both in vitro and in vivo, and is being developed as a novel class of anticancer drug. However, little is known about the mechanism by which YC-1 degrades HIF-1alpha. As the first step for understanding the mechanism of action of YC-1, we here identified the HIF-1alpha domain responsible for YC-1-induced protein degradation. YC-1 blocked the HIF-1alpha induction by hypoxia, iron chelation, and proteasomal inhibition and also degraded ectopically expressed HIF-1alpha. In deletion analyses, C-terminal HIF-1alpha was found to be sensitively degraded by YC-1. Using a GFP-fusion method, the YC-1-induced degradation domain was identified as the aa. 720-780 region of HIF-1alpha. We next tested the possible involvement of HDAC7 or OS-9 in YC-1-induced HIF-1alpha degradation. However, their binding to HIF-1alpha was not affected by YC-1, suggesting that they are not involved in the YC-1 action. It is also suggested that YC-1 targets a novel pathway regulating HIF-1alpha stability.
Kim
Hye-Lim
HL
Department of Pharmacology, Seoul National University College of Medicine, Chongno-gu, Seoul 110-799, Korea.
Yeo
Eun-Jin
EJ
Chun
Yang-Sook
YS
Park
Jong-Wan
JW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology*; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole