The role of CREB3L4 in the proliferation of prostate cancer cells

Abstract

The incidence of prostate cancer (PC) is growing rapidly throughout the world, in probable association with the adoption of western style diets. Thus, understanding the molecular pathways triggering the development of PC is crucial for both its prevention and treatment. Here, we investigated the role of the metabolism-associated protein, CREB3L4, in the proliferation of PC cells. CREB3L4 was upregulated by the synthetic androgen, R1881, in LNCaP PC cells (an androgen-dependent cell line). Knockdown of CREB3L4 resulted in decreased androgen-dependent PC cell growth. LNCaP cells transfected with siCREB3L4 underwent G2/M arrest, with upregulation of the proteins cyclin B1, phospho-CDK1, p21Waf1/Cip1, and INCA1, and downregulation of cyclin D1. Moreover, depletion of CREB3L4 resulted in significantly decreased expression of a subset of androgen-receptor (AR) target genes, including PSA, FKBP5, HPGD, KLK2, and KLK4. We also demonstrated that CREB3L4 directly interacts with the AR, and increases the binding of AR to androgen response elements (AREs). We also identified a role for the unfolded protein response (and its surrogate, IRE1α), in activating CREB3L4. Cumulatively, we postulate that CREB3L4 expression is mediated by an AR-IRE1α axis, but is also directly regulated by AR-to-ARE binding. Thus, our study demonstrates that CREB3L4 plays a key role in PC cell proliferation, which is promoted by both AR and IRE1α.

Overexpression of MUC1 predicts poor prognosis in patients with breast cancer

“…CREB3L4 is a principal correlated gene (Fig. 7A) that is abundantly expressed in prostate and breast cancer cell lines (43–45). Regression analysis revealed that MUC1 and CREB3L4 had high relevant coefficients (Spearman's correlation=0.60; Pearson's correlation=0.54) (Fig.…”

Increased prostaglandin-D2in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

“…It has been reported that HPGD is positively regulated by the androgen receptor (AR) (26) and that the AR is expressed by HL-1 cardiomyocytes (27). We observed that HPGD expression was significantly lower in control HL-1-STAT3-KD-CM compared to HL-1-ctrl-CM (Figs 2F and 2H).…”

“…In this context it has been shown that the AR can be activated by different ligands including interleukin (IL)-6 and testosterone (37). The AR is expressed in cardiomyocytes from various species including mouse and human (26, 38, 39) and STAT3 acts as a positive co-factor for AR signaling by directly interacting with amino acids 234-558 in the N-terminal domain of the AR (24). The AR is expressed on HL-1 cells and indeed, HPGD expression is lower in HL-1-STAT3-KD-CM compared to ctrl HL-1-CM.…”

The Novel Transcription Factor CREB3L4 Contributes to the Progression of Human Breast Carcinoma

“…As is typical of other ATF/CREB proteins, CREB3L4 contains a bZIP domain, which is located in its central region (amino acids 222-280). In humans, CREB3L4 is highly expressed in a variety of cancer types, including prostate carcinomas [11,19,20], hepatocellular carcinomas [21] and endometrial cancers [13]. Recently, it was revealed that the high messenger RNA (mRNA) expression of CREB3L4 was associated with reduced relapse-free survival (RFS) and diseasespecific survival (DSS) in BC [22].…”