TY - JOUR
T1 - HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells
AU - Causse, Sebastien Z.
AU - Marcion, Guillaume
AU - Chanteloup, Gaëtan
AU - Uyanik, Burhan
AU - Boudesco, Christophe
AU - Grigorash, Bogdan B.
AU - Douhard, Romain
AU - Dias, Alexandre M.M.
AU - Dumetier, Baptiste
AU - Dondaine, Lucile
AU - Gozzi, Gustavo J.
AU - Moussay, Etienne
AU - Paggetti, Jérôme
AU - Mirjolet, Céline
AU - de Thonel, Aurélie
AU - Dubrez, Laurence
AU - Demidov, Oleg N.
AU - Gobbo, Jessica
AU - Garrido, Carmen
N1 - Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2019/4/11
Y1 - 2019/4/11
N2 - A multicenter clinical study demonstrated the presence of a loss-of-function HSP110 mutation in about 15% of colorectal cancers, which resulted from an alternative splicing and was produced at the detriment of wild-type HSP110. Patients expressing low levels of wild-type HSP110 had excellent outcomes (i.e. response to an oxaliplatin-based chemotherapy). Here, we show in vitro, in vivo, and in patients’ biopsies that HSP110 co-localizes with DNA damage (γ-H2AX). In colorectal cancer cells, HSP110 translocates into the nucleus upon treatment with genotoxic chemotherapy such as oxaliplatin. Furthermore, we show that HSP110 interacts with the Ku70/Ku80 heterodimer, an essential element of the non-homologous end joining (NHEJ) repair machinery. We also demonstrate by evaluating the resolved 53BP1 foci that depletion in HSP110 impairs repair steps of the NHEJ pathway, which is associated with an increase in DNA double-strand breaks and in the cells’ sensitivity to oxaliplatin. HSP110-depleted cells sensitization to oxaliplatin-induced DNA damage is abolished upon re-expression of HSP110. Confirming a role for HSP110 in DNA non-homologous repair, SCR7 and NU7026, two inhibitors of the NHEJ pathway, circumvents HSP110-induced resistance to chemotherapy. In conclusion, HSP110 through its interaction with the Ku70/80 heterodimer may participate in DNA repair, thereby inducing a protection against genotoxic therapy.
AB - A multicenter clinical study demonstrated the presence of a loss-of-function HSP110 mutation in about 15% of colorectal cancers, which resulted from an alternative splicing and was produced at the detriment of wild-type HSP110. Patients expressing low levels of wild-type HSP110 had excellent outcomes (i.e. response to an oxaliplatin-based chemotherapy). Here, we show in vitro, in vivo, and in patients’ biopsies that HSP110 co-localizes with DNA damage (γ-H2AX). In colorectal cancer cells, HSP110 translocates into the nucleus upon treatment with genotoxic chemotherapy such as oxaliplatin. Furthermore, we show that HSP110 interacts with the Ku70/Ku80 heterodimer, an essential element of the non-homologous end joining (NHEJ) repair machinery. We also demonstrate by evaluating the resolved 53BP1 foci that depletion in HSP110 impairs repair steps of the NHEJ pathway, which is associated with an increase in DNA double-strand breaks and in the cells’ sensitivity to oxaliplatin. HSP110-depleted cells sensitization to oxaliplatin-induced DNA damage is abolished upon re-expression of HSP110. Confirming a role for HSP110 in DNA non-homologous repair, SCR7 and NU7026, two inhibitors of the NHEJ pathway, circumvents HSP110-induced resistance to chemotherapy. In conclusion, HSP110 through its interaction with the Ku70/80 heterodimer may participate in DNA repair, thereby inducing a protection against genotoxic therapy.
UR - http://www.scopus.com/inward/record.url?scp=85058397903&partnerID=8YFLogxK
U2 - 10.1038/s41388-018-0616-2
DO - 10.1038/s41388-018-0616-2
M3 - Article
C2 - 30542121
AN - SCOPUS:85058397903
SN - 0950-9232
VL - 38
SP - 2767
EP - 2777
JO - Oncogene
JF - Oncogene
IS - 15
ER -