Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation

Abstract

The molecular mechanisms of luminal cell differentiation are not understood well enough to determine how differentiation goes awry during oncogenesis. Using RNA-Seq analysis, we discovered that CREB1 plays a central role in maintaining new luminal cell survival and that oncogenesis dramatically changes the CREB1-induced transcriptome. CREB1 is active in luminal cells, but not basal cells. We identified ING4 and its E3 ligase, JFK, as CREB1 transcriptional targets in luminal cells. During luminal cell differentiation, transient induction of ING4 expression is followed by a peak in CREB1 activity, while JFK increases concomitantly with CREB1 activation. Transient expression of ING4 is required for luminal cell induction; however, failure to properly down-regulate ING4 leads to luminal cell death. Consequently, blocking CREB1 increased ING4 expression, suppressed JFK, and led to luminal cell death. Thus, CREB1 is responsible for the suppression of ING4 required for luminal cell survival and maintenance. Oncogenic transformation by suppressing PTEN resulted in constitutive activation of CREB1. However, the tumor cells could no longer fully differentiate into luminal cells, failed to express ING4, and displayed a unique CREB1 transcriptome. Blocking CREB1 in tumorigenic cells suppressed tumor growth in vivo , rescued ING4 expression, and restored luminal cell formation, but ultimately induced luminal cell death. IHC of primary prostate tumors demonstrated a strong correlation between loss of ING4 and loss of PTEN. This is the first study to define a molecular mechanism whereby oncogenic loss of PTEN, leading to aberrant CREB1 activation, suppresses ING4 expression causing disruption of luminal cell differentiation.

CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m6A-modified CREB1 mRNA

“…Moreover, qRT-PCR and Western blot assays showed that the mRNA and protein expression levels of CREB1’s target genes were downregulated in circEZH2-depleted HCT116 and SW620 cells (Additional file 10 : Fig. S3), including BCL-2, Cyclin A2, MMP-9 and GLUT3 [ 24 – 29 ]. RNA stability assays revealed that circEZH2 knockdown remarkably reduced the CREB1 mRNA stability in HCT116 and SW620 cells (Fig.…”

“…It has been well-established that cAMP response element-binding protein 1 (CREB1) belongs to a family of transcription factors whose activities are stimulated by increased intracellular cAMP [ 24 , 27 , 44 – 47 ]. Upon protein kinase A (PKA)-mediated reversible phosphorylation at serine 133 residue (Ser133ph), CREB1 can bind to DNA via a bZIP domain that recognizes cAMP response element (CRE; TGACGTCA or TGACG/CGTCA).…”

“…The cAMP responsiveness of CREB1 target genes, whose promoters contain CRE, is also dependent on the presence of TATA box in their promoters [ 48 ]. Compelling evidence demonstrates that CREB1 modulates the expression of proto-oncogenes, such as Cyclin A2, EGR-1, MMP2/9, GSK3A, non-coding RNAs, etc., which are associated with cell proliferation, differentiation, apoptosis, neovascularization, inflammatory response and tumorigenesis via the ERK1/2, PKA, PKC or CaMKII signaling pathways [ 24 – 26 , 28 , 29 , 49 ]. These reports strongly suggest the importance of genes constitutively regulated by CREB1 for their implicative involvement in promoting tumorigenesis and cancer progression.…”

CRISPR/Cas9-mediated deletion of Interleukin-30 suppresses IGF1 and CXCL5 and boosts SOCS3 reducing prostate cancer growth and mortality

“…Murine PC cells share a significant IL30-dependent upregulation of oncogenes, such as Abcb1a , that confers resistance to chemotherapy [ 58 ], Bcl2 , that rescues cancer cells from apoptosis and drives androgen-independent growth [ 59 ], Cav2 , which can activate cellular mitogenesis [ 60 ], and Creb1 , which regulates a network of genes required for cell survival, proliferation and migration [ 61 ]. In murine PC cells, IL30 also promotes the expression of Nfkb1 , the master regulator of immunity genes, cell-cycle modulators, survival signals, and of growth and angiogenic factors [ 62 ]; Rbp1 , which regulates retinoic acid (RA) homeostasis, and that is silenced in more than 40% of PCs [ 63 ]; Shbg , which regulates testosterone metabolism and supports cell growth [ 64 ]; and Tmprss2 , a membrane-anchored serine protease involved in PC progression, which can be found as TMPRSS2-ERG fusion gene in about 50% of PCs [ 65 ], and Vegfa , which promotes angiogenesis and metastasis [ 66 ].…”

ING Tumour Suppressors and ING Splice Variants as Coregulators of the Androgen Receptor Signalling in Prostate Cancer

“…ING4 expression is lost in more than a half of human primary prostate malignancies [2]. Moreover, ING4 loss is tightly correlated with loss of another tumour suppressor, PTEN, and associated with a dysfunctional differentiation program of basal epithelial cells resulting in prostate tumorigenesis [2,3]. Both malignant tissues isolated from PC patients and PC cell lines demonstrate decreased ING5 expression when compared to the non-malignant control [4].…”