Kinetochore genes are coordinately up-regulated in human tumors as part of a FoxM1-related cell division program.
The key player in directing proper chromosome segregation is the macromolecular kinetochore complex, which mediates DNA-microtubule interactions. Previous studies testing individual kinetochore genes documented examples of their overexpression in tumors relative to normal tissue, leading to proposals that up-regulation of specific kinetochore genes may promote tumor progression. However, kinetochore components do not function in isolation, and previous studies did not comprehensively compare the expression behavior of kinetochore components. Here we analyze the expression behavior of the full range of human kinetochore components in diverse published expression compendia, including normal tissues and tumor samples. Our results demonstrate that kinetochore genes are rarely overexpressed individually. Instead, we find that core kinetochore genes are coordinately regulated with other cell division genes under virtually all conditions. This expression pattern is strongly correlated with the expression of the forkhead transcription factor FoxM1, which binds to the majority of cell division promoters. These observations suggest that kinetochore gene up-regulation in cancer reflects a general activation of the cell division program and that altered expression of individual kinetochore genes is unlikely to play a causal role in tumorigenesis.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Prathapan
P
Thiru
Whitehead Institute for Biomedical Research, Cambridge, MA 02142Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
David M
DM
Kern
Whitehead Institute for Biomedical Research, Cambridge, MA 02142Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
Kara L
KL
McKinley
Whitehead Institute for Biomedical Research, Cambridge, MA 02142Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
Julie K
JK
Monda
Whitehead Institute for Biomedical Research, Cambridge, MA 02142Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
Florencia
F
Rago
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Kuan-Chung
KC
Su
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Tonia
T
Tsinman
Merrimack Pharmaceuticals, Cambridge, MA 02139.
Defne
D
Yarar
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
George W
GW
Bell
Whitehead Institute for Biomedical Research, Cambridge, MA 02142Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 icheese@wi.mit.edu.
Iain M
IM
Cheeseman
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018386:Kinetochores / Q000502:physiology*; D059467:Transcriptome; D015854:Up-Regulation
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors