An Ectopic Network of Transcription Factors Regulated by Hippo Signaling Drives Growth and Invasion of a Malignant Tumor Model

Abstract

Cancer cells have abnormal gene expression profiles; however, to what degree these are chaotic or driven by structured gene regulatory networks is often not known. Here we studied a model of Ras-driven invasive tumorigenesis in Drosophila epithelial tissues and combined in vivo genetics with next-generation sequencing and computational modeling to decipher the regulatory logic of tumor cells. Surprisingly, we discovered that the bulk of the tumor-specific gene expression is controlled by an ectopic network of a few transcription factors that are overexpressed and/or hyperactivated in tumor cells. These factors are Stat, AP-1, the bHLH proteins Myc and AP-4, the nuclear hormone receptor Ftz-f1, the nuclear receptor coactivator Taiman/SRC3, and Mef2. Notably, many of these transcription factors also are hyperactivated in human tumors. Bioinformatic analysis predicted that these factors directly regulate the majority of the tumor-specific gene expression, that they are interconnected by extensive cross-regulation, and that they show a high degree of co-regulation of target genes. Indeed, the factors of this network were required in multiple epithelia for tumor growth and invasiveness, and knockdown of several factors caused a reversion of the tumor-specific expression profile but had no observable effect on normal tissues. We further found that the Hippo pathway effector Yorkie was strongly activated in tumor cells and initiated cellular reprogramming by activating several transcription factors of this network. Thus, modeling regulatory networks identified an ectopic and ordered network of master regulators that control a large part of tumor cell-specific gene expression.

RETRACTED: Knockdown of Long Non-Coding RNA KCNQ1OT1 Restrained Glioma Cells’ Malignancy by Activating miR-370/CCNE2 Axis

“…Besides, a latest study shows CCNE2 is involved in regulation of Hippo pathway in breast cancer (Pegoraro et al, 2015). Hippo pathway is characterized as a tumor-suppressive axis, and plays important roles in tumor cellular process including proliferation, migration, invasion, and apoptosis (Alam et al, 2016; Atkins et al, 2016; Kemppainen et al, 2016; Mao et al, 2016). YAP is an important transcriptional activator and can be phosphorylated by Hippo pathway (Bouvier et al, 2016).…”

Nuclear receptors connect progenitor transcription factors to cell cycle control

“…In our work, abrupt expression levels were up-regulated in eye discs where there was forced maintenance of hth or hth + tsh (with a fold change of approximately 2 in both situations), suggesting also a role in the control of the expression of nuclear receptors in progenitors. More recently, overexpression of taiman and ftz - f1 was also shown to be present in a model of invasive cancer driven by RAS in the eye disc 68 . In the cancer models mentioned above, a role for the Hippo pathway has been described 66, 68 .…”

“…More recently, overexpression of taiman and ftz - f1 was also shown to be present in a model of invasive cancer driven by RAS in the eye disc 68 . In the cancer models mentioned above, a role for the Hippo pathway has been described 66, 68 . Therefore, a similar nuclear receptor (and probably abrupt ) expression pattern might be a general feature of Hippo-related tissue overgrowth.…”

Wingless signaling regulates winner/loser status in Minute cell competition

“…Indeed, blocking JNK signaling by over‐expressing the JNK phosphatase Puckered (Puc) significantly suppressed cell death at the nubbin/non‐nubbin boundary (Figure a, quantified in Figure e). It has been reported that cells with higher expression of dMyc, a crucial regulator of cell growth and cell cycle progression, outcompete surrounding cells with lower dMyc expression by supercompetition (de la Cova, Abril, Bellosta, Gallant, & Johnston, ; Moreno & Basler, ), and that over‐expression of dMyc suppresses cell competition triggered by cell polarity defect (Atkins et al., ). Intriguingly, however, over‐expression of dMyc in RpS3‐RNAi ‐expressing nubbin cells did not suppress cell death at the nubbin/non‐nubbin boundary (Figure b, quantified in Figure e).…”