Limits...
The basic helix-loop-helix transcription factor E47 reprograms human pancreatic cancer cells to a quiescent acinar state with reduced tumorigenic potential.

Kim S, Lahmy R, Riha C, Yang C, Jakubison BL, van Niekerk J, Staub C, Wu Y, Gates K, Dong DS, Konieczny SF, Itkin-Ansari P - Pancreas (2015)

Bottom Line: Moreover, induction of E47 in human PDA cells in vitro is sufficient to inhibit tumorigenesis.Human PDA cells retain a high degree of plasticity, which can be exploited to induce a quiescent acinar cell state with reduced tumorigenic potential.Moreover, bHLH activity is a critical node coordinately regulating human PDA cell growth versus cell fate.

View Article: PubMed Central - PubMed

Affiliation: From the *Development and Aging Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA; †Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; ‡Department of Pediatrics, University of California, San Diego, La Jolla, CA; §Department of Biological Sciences, Center for Cancer Research, the Bindley Bioscience Center, Purdue University, West Lafayette, IN; and ∥Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA.

ABSTRACT

Objectives: Pancreatic ductal adenocarcinoma (PDA) initiates from quiescent acinar cells that attain a Kras mutation, lose signaling from basic helix-loop-helix (bHLH) transcription factors, undergo acinar-ductal metaplasia, and rapidly acquire increased growth potential. We queried whether PDA cells can be reprogrammed to revert to their original quiescent acinar cell state by shifting key transcription programs.

Methods: Human PDA cell lines were engineered to express an inducible form of the bHLH protein E47. Gene expression, growth, and functional studies were investigated using microarray, quantitative polymerase chain reaction, immunoblots, immunohistochemistry, small interfering RNA, chromatin immunoprecipitation analyses, and cell transplantation into mice.

Results: In human PDA cells, E47 activity triggers stable G0/G1 arrest, which requires the cyclin-dependent kinase inhibitor p21 and the stress response protein TP53INP1. Concurrently, E47 induces high level expression of acinar digestive enzymes and feed forward activation of the acinar maturation network regulated by the bHLH factor MIST1. Moreover, induction of E47 in human PDA cells in vitro is sufficient to inhibit tumorigenesis.

Conclusions: Human PDA cells retain a high degree of plasticity, which can be exploited to induce a quiescent acinar cell state with reduced tumorigenic potential. Moreover, bHLH activity is a critical node coordinately regulating human PDA cell growth versus cell fate.

No MeSH data available.


Related in: MedlinePlus

Proposed model of mechanisms underlying E47/ID3 regulation of growth, acinar differentiation, and tumorigenicity in human PDA. Our working model is that high levels of ID3 contribute to tumorigenicity by inhibiting the bHLH transcriptional network. Conversely, E47 induces G0/G1 arrest via p21 and TP53INP1 induction and downregulation of cell cycle activators (eg, aurora kinase, topoisomerase, cyclinb2). Concurrently, E47 induces an acinar differentiation program that is characterized by re-expression of digestive enzymes, upregulation of Mist1, and its target genes and re-establishment of cell-cell junctions. Together, the combined activities of E47 constrain tumor growth.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4464938&req=5

Figure 6: Proposed model of mechanisms underlying E47/ID3 regulation of growth, acinar differentiation, and tumorigenicity in human PDA. Our working model is that high levels of ID3 contribute to tumorigenicity by inhibiting the bHLH transcriptional network. Conversely, E47 induces G0/G1 arrest via p21 and TP53INP1 induction and downregulation of cell cycle activators (eg, aurora kinase, topoisomerase, cyclinb2). Concurrently, E47 induces an acinar differentiation program that is characterized by re-expression of digestive enzymes, upregulation of Mist1, and its target genes and re-establishment of cell-cell junctions. Together, the combined activities of E47 constrain tumor growth.

Mentions: Collectively, our data establish for the first time that E47 reprograms aggressive PDA cells to a quiescent acinar state by restoring expression of p21, TP53INP1, acinar enzymes, and MIST1 (Fig. 6). Importantly, reprogramming greatly diminishes the tumor promoting potential of PDA cells, a finding with broad implications for therapeutic advancement for this highly lethal disease.


The basic helix-loop-helix transcription factor E47 reprograms human pancreatic cancer cells to a quiescent acinar state with reduced tumorigenic potential.

Kim S, Lahmy R, Riha C, Yang C, Jakubison BL, van Niekerk J, Staub C, Wu Y, Gates K, Dong DS, Konieczny SF, Itkin-Ansari P - Pancreas (2015)

Proposed model of mechanisms underlying E47/ID3 regulation of growth, acinar differentiation, and tumorigenicity in human PDA. Our working model is that high levels of ID3 contribute to tumorigenicity by inhibiting the bHLH transcriptional network. Conversely, E47 induces G0/G1 arrest via p21 and TP53INP1 induction and downregulation of cell cycle activators (eg, aurora kinase, topoisomerase, cyclinb2). Concurrently, E47 induces an acinar differentiation program that is characterized by re-expression of digestive enzymes, upregulation of Mist1, and its target genes and re-establishment of cell-cell junctions. Together, the combined activities of E47 constrain tumor growth.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4464938&req=5

Figure 6: Proposed model of mechanisms underlying E47/ID3 regulation of growth, acinar differentiation, and tumorigenicity in human PDA. Our working model is that high levels of ID3 contribute to tumorigenicity by inhibiting the bHLH transcriptional network. Conversely, E47 induces G0/G1 arrest via p21 and TP53INP1 induction and downregulation of cell cycle activators (eg, aurora kinase, topoisomerase, cyclinb2). Concurrently, E47 induces an acinar differentiation program that is characterized by re-expression of digestive enzymes, upregulation of Mist1, and its target genes and re-establishment of cell-cell junctions. Together, the combined activities of E47 constrain tumor growth.
Mentions: Collectively, our data establish for the first time that E47 reprograms aggressive PDA cells to a quiescent acinar state by restoring expression of p21, TP53INP1, acinar enzymes, and MIST1 (Fig. 6). Importantly, reprogramming greatly diminishes the tumor promoting potential of PDA cells, a finding with broad implications for therapeutic advancement for this highly lethal disease.

Bottom Line: Moreover, induction of E47 in human PDA cells in vitro is sufficient to inhibit tumorigenesis.Human PDA cells retain a high degree of plasticity, which can be exploited to induce a quiescent acinar cell state with reduced tumorigenic potential.Moreover, bHLH activity is a critical node coordinately regulating human PDA cell growth versus cell fate.

View Article: PubMed Central - PubMed

Affiliation: From the *Development and Aging Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA; †Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; ‡Department of Pediatrics, University of California, San Diego, La Jolla, CA; §Department of Biological Sciences, Center for Cancer Research, the Bindley Bioscience Center, Purdue University, West Lafayette, IN; and ∥Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA.

ABSTRACT

Objectives: Pancreatic ductal adenocarcinoma (PDA) initiates from quiescent acinar cells that attain a Kras mutation, lose signaling from basic helix-loop-helix (bHLH) transcription factors, undergo acinar-ductal metaplasia, and rapidly acquire increased growth potential. We queried whether PDA cells can be reprogrammed to revert to their original quiescent acinar cell state by shifting key transcription programs.

Methods: Human PDA cell lines were engineered to express an inducible form of the bHLH protein E47. Gene expression, growth, and functional studies were investigated using microarray, quantitative polymerase chain reaction, immunoblots, immunohistochemistry, small interfering RNA, chromatin immunoprecipitation analyses, and cell transplantation into mice.

Results: In human PDA cells, E47 activity triggers stable G0/G1 arrest, which requires the cyclin-dependent kinase inhibitor p21 and the stress response protein TP53INP1. Concurrently, E47 induces high level expression of acinar digestive enzymes and feed forward activation of the acinar maturation network regulated by the bHLH factor MIST1. Moreover, induction of E47 in human PDA cells in vitro is sufficient to inhibit tumorigenesis.

Conclusions: Human PDA cells retain a high degree of plasticity, which can be exploited to induce a quiescent acinar cell state with reduced tumorigenic potential. Moreover, bHLH activity is a critical node coordinately regulating human PDA cell growth versus cell fate.

No MeSH data available.


Related in: MedlinePlus