Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Pia Alhopuro; Mikael Bjorklund; Heli Sammalkorpi; Mikko Turunen; Sari Tuupanen; Mia Bistrom; Iina Niittymaki; Heli J. Lehtonen; Teemu Kivioja; Virpi Launonen; Juha Saharinen; Kari Nousiainen; Sampsa Hautaniemi; Kyosti Nuorva; Jukka-Pekka Mecklin; Heikki Jarvinen; Torben Orntoft; Diego Arango; Rainer Lehtonen; Auli Karhu; Jussi Taipale; Lauri A. Aaltonen

doi:10.1158/1541-7786.MCR-10-0086

Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Pia Alhopuro (Lead / Corresponding author)
, Mikael Bjorklund (Lead / Corresponding author)
, Heli Sammalkorpi
, Mikko Turunen
, Sari Tuupanen
, Mia Bistrom
, Iina Niittymaki
, Heli J. Lehtonen
, Teemu Kivioja
, Virpi Launonen
, Juha Saharinen
, Kari Nousiainen
, Sampsa Hautaniemi
, Kyosti Nuorva
, Jukka-Pekka Mecklin
, Heikki Jarvinen
, Torben Orntoft
, Diego Arango
, Rainer Lehtonen
, Auli Karhu

Jussi Taipale, Lauri A. Aaltonen (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

82 Citations (Scopus)

Abstract

The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. (C) 2010 AACR.

Original language	English
Pages (from-to)	952-960
Number of pages	9
Journal	Molecular Cancer Research
Volume	8
Issue number	7
DOIs	https://doi.org/10.1158/1541-7786.MCR-10-0086
Publication status	Published - Jul 2010

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

REPAIR-DEFICIENT CANCERS
TUMOR-SUPPRESSOR
PAS DOMAIN
CELL-CYCLE
SPECIFICITY
MECHANISM
PACEMAKER
MPER2
PLAYS

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10.1158/1541-7786.MCR-10-0086

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Alhopuro, P., Bjorklund, M., Sammalkorpi, H., Turunen, M., Tuupanen, S., Bistrom, M., Niittymaki, I., Lehtonen, H. J., Kivioja, T., Launonen, V., Saharinen, J., Nousiainen, K., Hautaniemi, S., Nuorva, K., Mecklin, J.-P., Jarvinen, H., Orntoft, T., Arango, D., Lehtonen, R., ... Aaltonen, L. A. (2010). Mutations in the Circadian Gene CLOCK in Colorectal Cancer. Molecular Cancer Research, 8(7), 952-960. https://doi.org/10.1158/1541-7786.MCR-10-0086

@article{648c964bda2343b5ab94ffd8e46abdbd,

title = "Mutations in the Circadian Gene CLOCK in Colorectal Cancer",

abstract = "The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53\% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. (C) 2010 AACR.",

keywords = "REPAIR-DEFICIENT CANCERS, TUMOR-SUPPRESSOR, PAS DOMAIN, CELL-CYCLE, SPECIFICITY, MECHANISM, PACEMAKER, MPER2, PLAYS",

author = "Pia Alhopuro and Mikael Bjorklund and Heli Sammalkorpi and Mikko Turunen and Sari Tuupanen and Mia Bistrom and Iina Niittymaki and Lehtonen, \{Heli J.\} and Teemu Kivioja and Virpi Launonen and Juha Saharinen and Kari Nousiainen and Sampsa Hautaniemi and Kyosti Nuorva and Jukka-Pekka Mecklin and Heikki Jarvinen and Torben Orntoft and Diego Arango and Rainer Lehtonen and Auli Karhu and Jussi Taipale and Aaltonen, \{Lauri A.\}",

year = "2010",

month = jul,

doi = "10.1158/1541-7786.MCR-10-0086",

language = "English",

volume = "8",

pages = "952--960",

journal = "Molecular Cancer Research",

issn = "1541-7786",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

Alhopuro, P, Bjorklund, M, Sammalkorpi, H, Turunen, M, Tuupanen, S, Bistrom, M, Niittymaki, I, Lehtonen, HJ, Kivioja, T, Launonen, V, Saharinen, J, Nousiainen, K, Hautaniemi, S, Nuorva, K, Mecklin, J-P, Jarvinen, H, Orntoft, T, Arango, D, Lehtonen, R, Karhu, A, Taipale, J & Aaltonen, LA 2010, 'Mutations in the Circadian Gene CLOCK in Colorectal Cancer', Molecular Cancer Research, vol. 8, no. 7, pp. 952-960. https://doi.org/10.1158/1541-7786.MCR-10-0086

TY - JOUR

T1 - Mutations in the Circadian Gene CLOCK in Colorectal Cancer

AU - Alhopuro, Pia

AU - Bjorklund, Mikael

AU - Sammalkorpi, Heli

AU - Turunen, Mikko

AU - Tuupanen, Sari

AU - Bistrom, Mia

AU - Niittymaki, Iina

AU - Lehtonen, Heli J.

AU - Kivioja, Teemu

AU - Launonen, Virpi

AU - Saharinen, Juha

AU - Nousiainen, Kari

AU - Hautaniemi, Sampsa

AU - Nuorva, Kyosti

AU - Mecklin, Jukka-Pekka

AU - Jarvinen, Heikki

AU - Orntoft, Torben

AU - Arango, Diego

AU - Lehtonen, Rainer

AU - Karhu, Auli

AU - Taipale, Jussi

AU - Aaltonen, Lauri A.

PY - 2010/7

Y1 - 2010/7

N2 - The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. (C) 2010 AACR.

AB - The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. (C) 2010 AACR.

KW - REPAIR-DEFICIENT CANCERS

KW - TUMOR-SUPPRESSOR

KW - PAS DOMAIN

KW - CELL-CYCLE

KW - SPECIFICITY

KW - MECHANISM

KW - PACEMAKER

KW - MPER2

KW - PLAYS

UR - https://www.scopus.com/pages/publications/77955438266

U2 - 10.1158/1541-7786.MCR-10-0086

DO - 10.1158/1541-7786.MCR-10-0086

M3 - Article

C2 - 20551151

SN - 1541-7786

VL - 8

SP - 952

EP - 960

JO - Molecular Cancer Research

JF - Molecular Cancer Research

IS - 7

ER -

Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Abstract

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Keywords

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