TY - JOUR
T1 - Induction of LEF1 by MYC activates the WNT pathway and maintains cell proliferation
AU - Hao, Yi Heng
AU - Lafita-Navarro, M. Carmen
AU - Zacharias, Lauren
AU - Borenstein-Auerbach, Nofit
AU - Kim, Min
AU - Barnes, Spencer
AU - Kim, Jiwoong
AU - Shay, Jerry
AU - Deberardinis, Ralph J.
AU - Conacci-Sorrell, Maralice
N1 - Funding Information:
This research was supported by CPRIT RR150059, ACS IRG-17-174-13, Welch I-1914, and UTSW Circle of Friends Early Investigator award to MCS and R35CA22044901 to RJD. MCS is the Virginia Murchison Linthicum Scholar in Medical Research.
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/10/17
Y1 - 2019/10/17
N2 - Background: While regulated WNT activity is required for normal development and stem cell maintenance, mutations that lead to constitutive activation of the WNT pathway cause cellular transformation and drive colorectal cancer. Activation of the WNT pathway ultimately leads to the nuclear translocation of β-catenin which, in complex with TCF/LEF factors, promotes the transcription of genes necessary for growth. The proto-oncogene MYC is one of the most critical genes activated downstream the WNT pathway in colon cancer. Here, we investigate the converse regulation of the WNT pathway by MYC. Methods: We performed RNA-seq analyses to identify genes regulated in cells expressing MYC. We validated the regulation of genes in the WNT pathway including LEF1 by MYC using RT-qPCR, Western blotting, and ChIP-seq. We investigated the importance of LEF1 for the viability of MYC-expressing cells in in fibroblasts, epithelial cells, and colon cells. Bioinformatic analyses were utilized to define the expression of MYC-regulated genes in human colon cancer and metabolomics analyses were used to identify pathways regulated by LEF1 in MYC expressing cells. Results: MYC regulates the levels of numerous WNT-related genes, including the β-catenin co-transcription factor LEF1. MYC activates the transcription of LEF1 and is required for LEF1 expression in colon cancer cells and in primary colonic cells transformed by APC loss of function, a common mutation in colon cancer patients. LEF1 caused the retention of β-catenin in the nucleus, leading to the activation of the WNT pathway in MYC-expressing cells. Consequently, MYC-expressing cells were sensitive to LEF1 inhibition. Moreover, we describe two examples of genes induced in MYC-expressing cells that require LEF1 activity: the peroxisome proliferator activated receptor delta (PPARδ) and the Acyl CoA dehydrogenase 9 (ACAD9). Conclusions: We demonstrated that MYC is a transcriptional regulator of LEF1 in colonic cells. Our work proposes a novel pathway by which MYC regulates proliferation through activating LEF1 expression which in turn activates the WNT pathway. Graphical Abstract: [Figure not available: see fulltext.]
AB - Background: While regulated WNT activity is required for normal development and stem cell maintenance, mutations that lead to constitutive activation of the WNT pathway cause cellular transformation and drive colorectal cancer. Activation of the WNT pathway ultimately leads to the nuclear translocation of β-catenin which, in complex with TCF/LEF factors, promotes the transcription of genes necessary for growth. The proto-oncogene MYC is one of the most critical genes activated downstream the WNT pathway in colon cancer. Here, we investigate the converse regulation of the WNT pathway by MYC. Methods: We performed RNA-seq analyses to identify genes regulated in cells expressing MYC. We validated the regulation of genes in the WNT pathway including LEF1 by MYC using RT-qPCR, Western blotting, and ChIP-seq. We investigated the importance of LEF1 for the viability of MYC-expressing cells in in fibroblasts, epithelial cells, and colon cells. Bioinformatic analyses were utilized to define the expression of MYC-regulated genes in human colon cancer and metabolomics analyses were used to identify pathways regulated by LEF1 in MYC expressing cells. Results: MYC regulates the levels of numerous WNT-related genes, including the β-catenin co-transcription factor LEF1. MYC activates the transcription of LEF1 and is required for LEF1 expression in colon cancer cells and in primary colonic cells transformed by APC loss of function, a common mutation in colon cancer patients. LEF1 caused the retention of β-catenin in the nucleus, leading to the activation of the WNT pathway in MYC-expressing cells. Consequently, MYC-expressing cells were sensitive to LEF1 inhibition. Moreover, we describe two examples of genes induced in MYC-expressing cells that require LEF1 activity: the peroxisome proliferator activated receptor delta (PPARδ) and the Acyl CoA dehydrogenase 9 (ACAD9). Conclusions: We demonstrated that MYC is a transcriptional regulator of LEF1 in colonic cells. Our work proposes a novel pathway by which MYC regulates proliferation through activating LEF1 expression which in turn activates the WNT pathway. Graphical Abstract: [Figure not available: see fulltext.]
KW - ACAD9
KW - Colon cancer
KW - LEF1
KW - MYC
KW - Metabolism
KW - PPARδ
KW - Proliferation
KW - Tumorigenesis
KW - WNT/β-catenin pathway
UR - http://www.scopus.com/inward/record.url?scp=85073605141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073605141&partnerID=8YFLogxK
U2 - 10.1186/s12964-019-0444-1
DO - 10.1186/s12964-019-0444-1
M3 - Article
C2 - 31623618
AN - SCOPUS:85073605141
SN - 1478-811X
VL - 17
JO - Cell Communication and Signaling
JF - Cell Communication and Signaling
IS - 1
M1 - 129
ER -