A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers

How cell numbers are determined is not understood. Hedgehog-Gli activity is involved in precursor cell proliferation and stem cell self-renewal, and its deregulation sustains the growth of many human tumours. However, it is not known whether GLI1, the final mediator of Hh signals, controls stem cell numbers, and how its activity is restricted to curtail tumourigenesis. Here we have altered the levels of GLI1 and p53, the major tumour suppressor, in multiple systems. We show that GLI1 expression in Nestin+ neural progenitors increases precursor and clonogenic stem cell numbers in vivo and in vitro. In contrast, p53 inhibits GLI1-driven neural stem cell self-renewal, tumour growth and proliferation. Mechanistically, p53 inhibits the activity, nuclear localisation and levels of GLI1 and in turn, GLI1 represses p53, establishing an inhibitory loop. We also find that p53 regulates the phosphorylation of a novel N' truncated putative activator isoform of GLI1 in human cells. The balance of GLI1 and p53 functions, thus, determines cell numbers, and prevalence of p53 restricts GLI1-driven stem cell expansion and tumourigenesis

Chimeric NANOG repressors inhibit glioblastoma growth in vivo in a context-dependent manner

Targeting stemness promises new therapeutic strategies against highly invasive tumors. While a number of approaches are being tested, inhibiting the core transcription regulatory network of cancer stem cells is an attractive yet challenging possibility. Here we have aimed to provide the proof of principle for a strategy, previously used in developmental studies, to directly repress the targets of a salient stemness and pluripotency factor: NANOG. In doing so we expected to inhibit the expression of so far unknown mediators of pro-tumorigenic NANOG function. We chose NANOG since previous work showed the essential requirement for NANOG activity for human glioblastoma (GBM) growth in orthotopic xenografts, and it is apparently absent from many adult human tissues thus likely minimizing unwanted effects on normal cells. NANOG repressor chimeras, which we name NANEPs, bear the DNA-binding specificity of NANOG through its homeodomain (HD), and this is linked to transposable human repressor domains. We show that in vitro and in vivo, NANEP5, our most active NANEP with a HES1 repressor domain, mimics knock-down (kd) of NANOG function in GBM cells. Competition orthotopic xenografts also reveal the effectiveness of NANEP5 in a brain tumor context, as well as the specificity of NANEP activity through the abrogation of its function via the introduction of specific mutations in the HD. The transcriptomes of cells expressing NANEP5 reveal multiple potential mediators of pro-tumorigenic NANEP/NANOG action including intercellular signaling components. The present results encourage further studies on the regulation of context-dependent NANEP abundance and function, and the development of NANEP-based anti-cancer therapies.This work was supported by a James McDonnell Brain Cancer Award, Fondation Eclosion funds and by the Département d’Instruction Publique de Genève to ARA. C.M. and M.K. were fellows of the ITN-EU networks CAPPELLA and HEALING, respectively

Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling

Prostate cancer is the most common solid tumor in men, and it shares with all cancers the hallmark of elevated, nonhomeostatic cell proliferation. Here we have tested the hypothesis that the SONIC HEDGEHOG (SHH)–GLI signaling pathway is implicated in prostate cancer. We report expression of SHH–GLI pathway components in adult human prostate cancer, often with enhanced levels in tumors versus normal prostatic epithelia. Blocking the pathway with cyclopamine or anti-SHH antibodies inhibits the proliferation of GLI1(+)/PSA(+) primary prostate tumor cultures. Inversely, SHH can potentiate tumor cell proliferation, suggesting that autocrine signaling may often sustain tumor growth. In addition, pathway blockade in three metastatic prostate cancer cell lines with cyclopamine or through GLI1 RNA interference leads to inhibition of cell proliferation, suggesting cell-autonomous pathway activation at different levels and showing an essential role for GLI1 in human cells. Our data demonstrate the dependence of prostate cancer on SHH–GLI function and suggest a novel therapeutic approach

Correction: Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling.

[This corrects the article DOI: 10.1371/journal.pone.0150697.]

Context-dependent Regulation of the GLI Code in Cancer by HEDGEHOG and Non-HEDGEHOG Signals

A surprisingly large and unrelated number of human tumors depend on sustained HEDGEHOG-GLI (HH-GLI) signaling for growth. This includes cancers of the skin, brain, colon, lungs, prostate, blood and pancreas among others. The basis of such commonality is not obvious. HH-GLI signaling has also been shown to be active in and required for cancer stem cell survival and expansion in different cancer types, and its activity is essential not only for tumor growth but also for recurrence and metastatic growth, two key medical problems. Here we review recent data on the role of HH-GLI signaling in cancer focusing on the role of the GLI code, the regulated combinatorial and cooperative function of repressive and activating forms of all Gli transcription factors, as a signaling nexus that integrates not only HH signals but also those of multiple tumor suppressors and oncogenes. Recent data support the view that the context-dependent regulation of the GLI code by oncogenes and tumor suppressors constitutes a basis for the widespread involvement of GLI1 in human cancers, representing a perversion of its normal role in the control of stem cell lineages during normal development and homeostasis