IER3 is a crucial mediator of TAp73β-induced apoptosis in cervical cancer and confers etoposide sensitivity

Abstract

Infection with high-risk human papillomaviruses (HPVs) causes cervical cancer. E6 oncoprotein, an HPV gene product, inactivates the major gatekeeper p53. In contrast, its isoform, TAp73β, has become increasingly important, as it is resistant to E6. However, the intracellular signaling mechanisms that account for TAp73β tumor suppressor activity in cervix are poorly understood. Here, we identified that IER3 is a novel target gene of TAp73β. In particular, TAp73β exclusively transactivated IER3 in cervical cancer cells, whereas p53 and TAp63 failed to do. IER3 efficiently induced apoptosis, and its knockdown promoted survival of HeLa cells. In addition, TAp73β-induced cell death, but not p53-induced cell death, was inhibited upon IER3 silencing. Moreover, etoposide, a DNA-damaging chemotherapeutics, upregulated TAp73β and IER3 in a c-Abl tyrosine kinase-dependent manner, and the etoposide chemosensitivity of HeLa cells was largely determined by TAp73β-induced IER3. Of interest, cervical carcinomas from patients express no observable levels of two proteins. Thus, our findings suggest that IER3 is a putative tumor suppressor in the cervix, and the c-Ab1/p73β/IER3 axis is a novel and crucial signaling pathway that confers etoposide chemosensitivity. Therefore, TAp73β and IER3 induction would be a valuable checkpoint for successful therapeutic intervention of cervical carcinoma patients.

Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers

“…This pattern is highly reminiscent of the product of the immediate early gene X1 (IEX-1/IER3), which was previously reported to sequester MCL-1 in response to DNA damage [ 25 ], at least partially co-localizing with PML bodies in HeLa cervical carcinoma cells [ 26 ]. In this cell line, upregulation of IER3 was required for DNA damage to induce apoptosis [ 27 ]. Intriguingly, we found IER3 to be strongly induced upon conditional EWS-FLI1 knockdown in A673/TR/shEF (Figure 4E ) and, with the only exception of SK-N-MC, in four of five additional cell lines upon transient knockdown of EWS-FLI1 [ 23 ].…”

Integrated Hypothalamic Transcriptome Profiling Reveals the Reproductive Roles of mRNAs and miRNAs in Sheep

“…Cyclin-dependent kinase 3 (CDK3), targeted by Novel_237, was reported that the downregulation of activities of CDK3-related kinase could promote cell apoptosis in the rat (Braun et al, 1998). Immediate early response 3 (IER3), targeted by Novel_327, was also involved in enhancing (Zhou et al, 2017) or mediating (Jin et al, 2015) cell apoptosis. Polycystic kidney and hepatic disease gene 1 (PKHD1), targeted by Novel_401, has been discovered to induce cell apoptosis, after being downregulated through the PI3K and NF-kB pathways (Sun et al, 2011).…”

Identification and validation of a six-gene signature associated with glycolysis to predict the prognosis of patients with cervical cancer

“…6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), is a key kinase in Warburg pathway [ 34 ], has been found to be associated with a variety of cancers, including breast cancer [ 35 ], prostate cancer [ 36 ] and glioblastoma [ 37 ], promoting the progression and metastasis of cancer, and may become an effective molecular target of anti-tumor drugs. It was found that the expression of immediate early response gene 3 (IER3) was increased in advanced cancer [ 38 , 39 ], but some studies have found that IER3 can also promote tumour cell apoptosis and has anti-tumour activity, such as lower expression in CC tissues [ 40 ], and increasing the expression of IER3 can enhance the sensitivity of CC cells to radiotherapy [ 41 ]. In contrast, in our study, we found that IER3 exists as a risk factor.…”