Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: potential role of histone deacetylase 6.
OBJECTIVE
Histone deacetylase inhibitors (HDIs) are prototypes of agents targeting epigenetic modifications and have received considerable attention for their promise as targeted anticancer drugs. We examined the effects and potential mechanism(s) of combining LBH589 and irradiation in human cancer cells having activated EGFR or HER-2 signaling, focusing on the role of HDAC6.


METHODS
We evaluated whether the HDI, LBH589, would radiosensitize a panel of human tumor cell lines having activated EGFR or HER-2 signaling. A mechanistic role for the HDAC6 isotype was investigated using RNA interference and ectopic overexpression HDAC6.


RESULTS
The HDI, LBH589, enhanced the radiosensitivity of the human carcinoma cell lines we tested. Radiosensitization was accompanied by abrogation of radiation-induced G2/M arrest and was associated with aberrant mitotic features and prolonged gammaH2AX foci. Radiation-induced apoptosis was also increased. LBH589 radiosensitized cells with activated EGFR or HER-2 signaling to a greater degree than the HDIs SK7041 or TSA. However radiosensitization by the three HDI was equivalent in cells without activation of this signaling. LBH589 led acetylation of histone H3 and HSP90. This was associated with down-regulation of the client oncoproteins EGFR, HER-2, and decreased phosphorylation of Akt and ERK. Specific inhibition of HDAC6 by RNAi increased radiosensitivity as well as increasing acetylation of HSP90 and reducing the association of HSP90 with its client proteins. Conversely, ectopic overexpression of HDAC6 isotype increased the levels of p-EGFR and p-AKT expression, and reduced LBH589-mediated radiosensitization.


CONCLUSIONS
These findings define a unique mechanism for counteracting pro-survival signaling from EGFR or HER-2 that is present in many tumor cells.
Kim
In Ah
IA
Department of Radiation Oncology, Seoul National University School of Medicine, Seoul, Republic of Korea. inah228@snu.ac.kr
No
Mina
M
Lee
Jang Mi
JM
Shin
Jin Hee
JH
Oh
Jee Sun
JS
Choi
Eun Jung
EJ
Kim
Il Han
IH
Atadja
Peter
P
Bernhard
Eric J
EJ