Intracellular CD24 disrupts the ARF–NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation

Abstract

CD24 is over-expressed in nearly 70% human cancers while TP53 is the most frequently mutated tumor suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and shRNA silencing of CD24 retard the growth, progression, and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2, and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.

Silencing of CD24 Enhances the PRIMA-1–Induced Restoration of Mutant p53 in Prostate Cancer Cells

“…To validate the role of CD24 in tumor progression and metastasis in PCa, we crossed the CD24 -null allele (12) into transgenic adenocarcinoma mouse prostate (TRAMP) mice, a strain that develops spontaneous PCas (13). The results showed that targeted mutation of CD24 retards the growth, progression, and metastasis of PCa cells (6), supporting a role of CD24 in tumor progression and metastasis. In addition, CD24 is highly expressed in hematopoietic cells and is involved in both adaptive and innate immunity (14), which may contribute to tumor progression and metastasis.…”

“…Notably, CD24 serves as a marker for poor prognosis of human cancers (1), including prostate cancers (PCas) (2, 3). Analyses involving ectopic and/or inducible expression (4–7), targeted mutations (6, 8, 9), gene silencing (4, 6, 7, 10), and antibody blocking (11) demonstrate the oncogenic function of CD24. Our recent study showed that intracellular CD24 is sufficient to promote cell proliferation in PCa cells (6).…”

“…Analyses involving ectopic and/or inducible expression (4–7), targeted mutations (6, 8, 9), gene silencing (4, 6, 7, 10), and antibody blocking (11) demonstrate the oncogenic function of CD24. Our recent study showed that intracellular CD24 is sufficient to promote cell proliferation in PCa cells (6). Furthermore, the effects of CD24 on tumor progression and metastasis have been demonstrated with xenogenic (4–7, 9) and transgenic tumor models (6, 8).…”

“…Our recent study showed that intracellular CD24 is sufficient to promote cell proliferation in PCa cells (6). Furthermore, the effects of CD24 on tumor progression and metastasis have been demonstrated with xenogenic (4–7, 9) and transgenic tumor models (6, 8). To validate the role of CD24 in tumor progression and metastasis in PCa, we crossed the CD24 -null allele (12) into transgenic adenocarcinoma mouse prostate (TRAMP) mice, a strain that develops spontaneous PCas (13).…”

Siglec-G represses DAMP-mediated effects on T cells

“…CD24 is reported to be expressed in solid tumors (29) and associated with tumor growth and metastasis (30,31) caused by p53 inactivation (32). Therefore, CD24 stimulation might potentially increase the risk of relapse and cause unexpected toxicities.…”