CD24 Is an Effector of HIF-1–Driven Primary Tumor Growth and Metastasis

Abstract

Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor HIF-1α in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element (HRE) in the CD24 promoter. HIF-1α overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the CD24 promoter. shRNA mediated-attenuation of HIF-1α or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1α-depleted cancer cells rescued this decrease while HIF-1α overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and CD24 levels and an association of their co-expression to decreased patient survival. Our results establish a mechanistic linkage between two critically important molecules in cancer, identifying CD24 as a critical HIF-1α transcriptional target and biological effector, strengthening the rationale to target CD24 for cancer therapy.

CD24 expression is important in male urothelial tumorigenesis and metastasis in mice and is androgen regulated

“…Two previously published CD24 promoter sequences (42,43) showed considerable mismatch between each other and a partial promoter from GenBank. Therefore we cloned and sequenced the CD24 promoter from several distinct human cell lines to identify a common sequence for our studies as described (44). The sequences can be found in GenBank with the following accession numbers: UM-UC-3 CD24 promoter, JN565036; J82 CD24 promoter, JN565037; LNCaP CD24 promoter, JN565040; LuL-2 CD24 promoter, JN565041; and EJ CD24 promoter, JN565042.…”

Global Gene Repression by the Steroid Receptor Coactivator SRC-1 Promotes Oncogenesis

“…Here, we identified the differentiation marker CD24 and the apoptotic protein PAWR as direct SRC1/ HOXC11 suppression targets. CD24 has been identified as a transcriptional target gene for hypoxia-inducible factor-1a (HIF-1a) and has been linked to HIF-1a-mediated tumor growth in both primary and metastatic tumors (25). Functions of CD24, however, may depend on the cellular context, in particular with regard to endocrine cancer.…”

Real-time dynamics of methyl-CpG-binding domain protein 3 and its role in DNA demethylation by fluorescence correlation spectroscopy

“…[34][35][36] To some extent, low oxygen tension is critical for cancer stem cell maintenance and therefore responsible for fatal tumor progression and reoccurrence. 37,38 A past study has shown that culturing of mouse and human fibroblasts under hypoxia can improve the reprogramming efficiency of the induced pluripotent stem cell (iPS). 39 It has also been reported that stem cells possess low level of global methylation compared with terminally differentiated cells.…”