SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization

Abstract

Steroid receptor coactivator 3 (SRC-3) is an oncogenic nuclear receptor coactivator that plays a significant role in drug resistance. Using a lentiviral cDNA library rescue screening approach, we identified a SRC-3 downstream gene-TRAF4 (tumor necrosis factor [TNF] receptor associated-factor 4)-that functions in cell resistance to cytotoxic stress. TRAF4 expression is positively correlated with SRC-3 expression in human breast cancers. Similar to that observed for SRC-3 overexpression, breast cancer cells overexpressing TRAF4 are more resistant to stress-induced death. Here, we further dissected the underlying molecular mechanism for SRC-3 and TRAF4-mediated resistance to cytotoxic agents. We observed that SRC-3 expression is inversely correlated with the expression of p53-regulated proapoptotic genes in breast cancers and further found that SRC-3 and TRAF4 overexpression diminished cytotoxic stress-induced up-regulation of the tumor suppressor p53 protein.To determine the mechanism, we showed that the TRAF domain of TRAF4 bound to the N-terminal TRAF-like region of the deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease; also named USP7) and blocked the access of p53 to the same region of HAUSP. This TRAF4-mediated inhibition of HAUSP then led to the loss of p53 deubiquitination and its stabilization in response to cellular stress. Consistent with this cellular function, we also found that TRAF4 overexpression in breast cancer patients was associated significantly with poor prognosis. Because of SRC-3's ability to abrogate p53 function, our results suggest that SRC-3 overexpression may be especially important in tumors in which p53 is not mutated.

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

“…Forced overexpression of SRC-3 in mammary epithelial cells has been shown to be sufficient to promote mammary tumor formation, directly indicating it in breast cancer initiation (Lanz et al, 2010). Consistently, mice with SRC-3 deletion had suppressed oncogene-and carcinogen-induced breast cancer initiation, progression, and metastasis (Kuang et al, 2004;Yi et al, 2013). Moreover, overexpression of SRC-3 has been frequently observed in a variety of other cancer types including lung, ovarian, liver, colorectal, pancreatic, and prostate cancers (Long et al, 2012;Palmieri et al, 2013;Geng et al, 2013).…”

The phosphoinositide-binding protein TRAF4 modulates tight junction stability and migration of cancer cells

“…Indeed, TRAF4 was shown to bind and inactivate the deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease). 20 HAUSP antagonizes the action of MDM2 on P53. While the E3-ligase MDM2 ubiquitinates p53 to induce its proteasomal degradation, HAUSP deubiquitinates P53 and stabilizes the protein.…”

“…Once TJ are destroyed, TRAF4 is more abundant in the cytoplasm and/or in the nucleus 8,9,16,20 ; its role in these compartments remained unclear. A recent study addressed the role of TRAF4 in signaling events occurring in the cytoplasm and in the nucleus.…”

“…16 Interestingly, in mammary cancer cells, TRAF4 localization is altered: while it is still present in TJs in well differentiated tumors, the protein is relocalized in the cytoplasm and the nucleus in poorly differentiated tumors, indicating that TRAF4 functions differently in cancer cells. 8,9,16,20 TRAF4 is a typical TRAF protein composed of 3 distinct modular domains, an N-terminal RING domain, a succession of 7 zinc fingers (ZF), and a C-terminal TRAF domain. 15 The RING domain of TRAF4 was shown to confer an E3-ligase activity to the protein, the 7 central ZF have an unknown function but, by analogy with other TRAF proteins, are most probably involved in protein-protein interactions, and the TRAF domain governs the trimerization of the protein.…”

Steroid receptor coactivator-3 is a pivotal target of gambogic acid in B-cell Non-Hodgkin lymphoma and an inducer of histone H3 deacetylation

“…One previous research also demonstrated GA restrains the growth of xenografted GCB-and ABC-DLBCL cells in nude mice (Shi et al, 2015). In consideration of the therapy-resistant role of overexpressed SRC-3, inhibition of SRC-3 was also required in cancer chemotherapy especially for those chemoresistant cancers (Colo et al, 2007;Tien and Xu, 2012;Yi et al, 2013). GA could be used in combination with conventional chemotherapy to relieve the chemoresistance of cancer.…”