Cancer Research in Switzerland - Krebsliga Schweiz

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Results
The induction of viral proteins, the overexpression of
PP2Ac or the infection of Huh7.5 cells with HCVcc resulted
in an inhibition of histone H4 methylation/acetylation
and histone H2AX phosphorylation in a significantly
changed expression of genes important for hepatocarcinogenesis
and inhibited DNA damage repair. These
changes were partially reversed by the treatment of cells
with the methyl­group donor S­adenosyl­L­methionine
(SAMe).
Conclusion
The correction of defective histone modifications by Sadenosyl­L­methionine
makes this drug a candidate for
chemo­preventive therapies in patients with chronic hepatitis
C who are at risk for developing hepatocellular carcinoma.
Project coordinator
Prof. Dr. Markus Hermann Heim
Klinik für Gastroenterologie und Hepatologie
Universitätsspital Basel
Petersgraben 4
CH­4031 Basel
Phone +41 (0)61 265 51 74
markus.heim@unibas.ch
Hemmings Brian A. | Role of protein kinase B (PKB/Akt)
in cell transformation and cancer
(OCS 01667­02­2005)
Conserved from primitive metazoans to humans, the serine/threonine
protein kinase B (PKB, also known as Akt)
belongs to the AGC group of protein kinases and has
emerged as a critical signalling molecule as a mediator of
the phosphoinositide 3­kinase (PI3K) pathway. Activated
upon PI3K signalling, PKB phosphorylates a wide range of
substrates influencing diverse cellular and physiological
processes, including cell cycle progression, cell growth
and differentiation, cell survival/suppression of apoptosis,
metabolism, angiogenesis and motility. As one of central
node of signalling pathways, hyperactivation of PKB in
most types of human cancers has been extensively studied
towards an effective cancer therapy.
Our research work led to the discovery of DNA­dependent
protein kinase (DNA­PK) as a novel upstream kinase
of PKB. We showed that PKB interacts and is phosphorylated
by DNA­PK adjacent to DNA­double­strand breaks
induced by g­irradiation, thus protecting the cell from
DNA­damage­induced apoptosis. In addition, we also investigated
the mechanisms of how activated PKB signalling
inhibits p53 activity during DNA damage. We identified
a novel PKB substrate, Twist1, a basic helix­loop­helix
transcription factor that is phosphorylated by PKB on serine
42 (S42) when the cells are exposed to g­irradiation
or genotoxic drug Adriamycin. S42 phosphorylation of
Twist1 inhibits p53 activity. Mutation of S42 to alanine
to prevent PKB­mediated phosphorylation sensitizes cells
to DNA damage. Moreover, phosphorylation of Twist1
was demonstrated in various human cancer tissues, suggesting
that this posttranslational modification ensures
functional activation of Twist1 following promotion of
survival during carcinogenesis. In parallel and in collaboration
with other laboratories, we showed that the promyelocytic
leukaemia (PML) tumour suppressor protein
was activated by homeodomain­interacting protein kinase
(HIPK2) in early stage responses to DNA damage.
Overexpression of Twist1 has been reported in 21 cancer
types including breast cancer, melanoma and prostate
cancer, and correlates with poor prognosis in clinic.
We showed that Twist1 phosphorylation on S42 promotes
full epithelial­mesenchymal transition and this modification
is essential for breast cancer metastasis to the lung
in a mouse model. Furthermore, 1,532 invasive breast tumour
samples were examined and revealed Twist1 phosphorylation
in over 90 % of these tumour samples, including
both invasive ductal and invasive lobular carcinomas,
indicating an important regulatory role of Twist1 phosphorylation
in cancer invasion and metastasis. As Twist1
does not seem to be active postnatally in human physiology
but is deregulated during tumour progression, we are
continuing to investigate if phosphorylated Twist1 may be
a novel biomarker for tumour metastasis and a potential
therapeutic target for metastatic cancers.
Project coordinator
Dr. Brian A. Hemmings
Friedrich Miescher Institut für
biomedizinische Forschung (FMI)
Maulbeerstrasse 66
CH­4058 Basel
Phone +41 (0)61 697 48 72
Fax +41 (0)61 697 39 76
brian.hemmings@fmi.ch
Hemmings Brian A. | The role of human protein
kinase NDR in cell morphogenesis, cell division,
growth control and cancer (OCS­01942­08­2006)
The NDR proteins family is a group of serine/threonine kinases
that is conserved from yeast to man. They are members
of the AGC kinase family and include molecules such
as LATS, Cbk1, Orb6, Cot­1 and Dbf2. In budding yeast
Dbf2 is an integral part of the mitotic MEN network, and
Cbk1 is required for the regulation of morphological
changes. Recent genetic studies have resulted in the isolation
of various important factors controlling these processes.
Significantly, these studies have also shown that
the yeast counterparts of NDR interact with Mob1 and
Mob2. These interactions are very important, since they
are essential for the activity and biological function of
these yeast kinases.
Based on these findings our laboratory could show that
the interaction between human MOB1 (hMOB1) and
MOB2 (hMOB2) with the human NDR and LATS kinases
plays a decisive role. By testing mutants of hMOB1,
hMOB2, NDR and LATS, we observed that a direct interaction
between hMOB1 and NDR or LATS is needed to
ensure activation of these kinases, while the interaction of