Estrogen-Mediated Upregulation of Noxa Is Associated with Cell Cycle Progression in Estrogen Receptor-Positive Breast Cancer Cells

Abstract

Noxa is a Bcl-2-homology domain (BH3)-only protein reported to be a proapoptotic member of the Bcl-2 family. Estrogen has been well documented to stimulate cell growth and inhibit apoptosis in estrogen receptor (ER)-positive breast cancer cells. Intriguingly, recent reports have shown that 17β-estradiol (E2) induces Noxa expression, although the mechanisms underlying E2-mediated induction of Noxa and its functional significance are unknown. Using MCF7 human breast cancer cells as an experimental model, we show that Noxa is upregulated by E2 via p53-independent processes that involve c-Myc and ERα. Experiments using small interfering ribonucleic acids (siRNA) to specifically knock down p53, c-Myc, and ERα demonstrated that c-Myc and ERα, but not p53, are involved in the transcriptional upregulation of Noxa following E2 treatment. Furthermore, while E2 promoted the recruitment of c-Myc and ERα to the NOXA promoter in chromatin immunoprecipitation (ChIP) assays, E2 did not induce p53 recruitment. Interestingly, E2-mediated upregulation of Noxa was not associated with apoptosis. However, siRNA-mediated knockdown of Noxa resulted in cell cycle arrest in G0/G1-phase and significantly delayed the G1-to-S-phase transition following E2 treatment, indicating that Noxa expression is required for cell cycle progression in ER-positive breast cancer cells.

BAK and NOXA Are Critical Determinants of Mitochondrial Apoptosis Induced by Bortezomib in Mesothelioma

“…However, it has been shown that in different cellular systems the up-regulation of Noxa at both protein and mRNA level induced by bortezomib can also occur through p53-independent mechanisms [22], [34], [37], [38], such as myc transcriptional regulation [24]. Indeed, it was demonstrated that c-Myc can bind the Noxa promoter and regulate its transcription [24], [39]. As shown in Figure 6, Noxa overexpression occurs in REN cells upon treatment with bortezomib.…”

SNF5 Reexpression in Malignant Rhabdoid Tumors Regulates Transcription of Target Genes by Recruitment of SWI/SNF Complexes and RNAPII to the Transcription Start Site of Their Promoters

“…In this study, we showed that NOXA expression in MRT cell lines inhibited growth as efficiently as hSNF5 reexpression. Although several reports have shown NOXA as a positive growth regulator, taken together, these data implicate NOXA expression as a contributor to the strong growth inhibition induced by hSNF5 reexpression (34, 35). Alternately, hSNF5 loss may result in a failure to regulate NOXA expression in the case of DNA damage by some chemotherapy agents such as doxorubicin.…”

NOXA contributes to the sensitivity of PERK‐deficient cells to ER stress

“…While NOXA is well known for its role as a pro‐apoptotic member of the BCL‐2 family, it has become increasingly evident that NOXA plays important roles in other cellular processes. NOXA expression is upregulated upon estrogen stimulation and is required for cell cycle progression in estrogen receptor‐positive breast cancer cells [26]. NOXA has also been shown to promote cell growth by stimulating glucose consumption via the pentose phosphate pathway [27].…”