The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 225

and early mortality among cancer patients. After adjusting for other factors
that might affect survival, circadian rhythm in salivary and serum cortisol
levels as well as daily rest/activity patterns are used as independent prognosis
factors for survival and therapeutic response of patients with metastatic
breast, lung, and colorectal cancers. 54-61

2.3. Disruption of the molecular clockworks in human cancers
Ample evidence has linked dysfunction of the molecular clock with patho-
genesis of human cancers ( Table 9.1 ). The mechanisms of dysregulation of
the core circadian genes in human cancers discovered to date include epi-
genetic silencing by promoter methylation, deregulation at the transcrip-
tional and posttranscriptional levels, and structural variations of clock
proteins due to circadian gene polymorphisms.
In comparison to normal host tissues, decreased expression and polymor-
phism of the core circadian genes Per1 , Per2 , and Per3 are frequently found in
human breast, endometrial, prostate, pancreatic, colorectal, and nonsmall
cell lung cancers (NSCLC), as well as hepatocellular carcinoma, neck squa-
mous cell carcinoma, glioma, AML, and chronic myeloid lymphoma
(CML). 62,63,80,85,86,88,90,91,98,99,102,103 In CML, breast, endometrial, and
NSCLC, this deregulation is often linked to hypermethylation of CpG
islands or aberrant acetylation in the promoters of Per genes, which leads
to gene silencing. 64,78,84,91,100 Other core circadian genes are also frequently
deregulated or silenced in human cancers. For example, the epigenetic inac-
tivation of Bmal1 is often linked to hematologic malignancies including
NHL, diffuse large B-cell lymphoma, acute lymphocytic leukemia (ALL),
and AML, whereas polymorphisms in Clock , Cry1 , Cry2 , and Npas2
gene are often found to be associated with an increased risk or recurrence
of NHL, AML, endometrial ovarian, colorectal, and breast can-
cers. 65,75,81,84,94,104 In most studies examining the role of the molecular
clock in human cancers, deregulation or polymorphism of multiple or
all core circadian genes is observed. For example, deregulation or polymor-
phism of Per1 , Per2 , and Per3 , Clock , Bmal1 , Cry1 , Cry2 , Clock , Npas2 , and/
or CK1e

is often found in human CML, prostate, pancreatic and epithelial
ovarian cancers, leukemia, pleural mesothelioma, hepatocellular carcinoma,
glioma, and neck squamous cell carcinoma. 76,78,87,89,92,93,95,96,99,101,104
Based on these discoveries, a combined deregulation of Cry1 and Bmal1 ,
or Cry1 and Per2 , has been suggested as a negative prognostic marker for epi-
thelial ovarian cancer and CML, respectively. 76,77,96