TY - JOUR
T1 - Pan-cancer analyses reveal genomic features of FOXM1 overexpression in cancer
AU - Barger, Carter J.
AU - Branick, Connor
AU - Chee, Linda
AU - Karpf, Adam R.
N1 - Funding Information:
Funding: This work was supported by The Fred & Pamela Buffett Cancer Center, NCI P30 CA036727, NIH T32CA009476, NIH/NCI F99CA212470, and a UNMC Program of Excellence Assistantship.
Funding Information:
This work was supported by The Fred & Pamela Buffett Cancer Center, NCI P30 CA036727, NIH T32CA009476, NIH/NCI F99CA212470, and a UNMC Program of Excellence Assistantship. The authors thank the UNMC Epigenomics, Genomics and Flow Cytometry Core Facilities. We thank David Klinkebiel for assistance with RNA-seq data and data deposits, and Mustafa Albahrani for assistance with CCLE data. We thank Nicholas Mullen for assistance with RT-qPCR. We thank Pradip Raychaudhuri (University of Illinois at Chicago) for the 6X-FOXM1 promoter reporter construct, Angela Tyner for the PGL3-FOXM1 promoter reporter construct and Rene Medema (Netherlands Cancer Institute) for the pFlash-FOXM1 promoter reporter construct.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/2
Y1 - 2019/2
N2 - FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer.
AB - FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer.
KW - Basal breast cancer
KW - FOXM1
KW - Fallopian tube epithelial cells
KW - Gene amplification
KW - Genomic instability
KW - High-grade serous ovarian cancer
KW - Pan-cancer
KW - Retinoblastoma protein cyclin E1
KW - Testicular germ cell tumors
UR - http://www.scopus.com/inward/record.url?scp=85063579790&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063579790&partnerID=8YFLogxK
U2 - 10.3390/cancers11020251
DO - 10.3390/cancers11020251
M3 - Article
C2 - 30795624
AN - SCOPUS:85063579790
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 2
M1 - 251
ER -