TY - JOUR
T1 - TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer
AU - Banerjee, Rajat
AU - Russo, Nickole
AU - Liu, Min
AU - Basrur, Venkatesha
AU - Bellile, Emily
AU - Palanisamy, Nallasivam
AU - Scanlon, Christina S.
AU - Van Tubergen, Elizabeth
AU - Inglehart, Ronald C.
AU - Metwally, Tarek
AU - Mani, Ram Shankar
AU - Yocum, Anastasia
AU - Nyati, Mukesh K.
AU - Castilho, Rogerio M.
AU - Varambally, Sooryanarayana
AU - Chinnaiyan, Arul M.
AU - D'Silva, Nisha J.
PY - 2014/7/31
Y1 - 2014/7/31
N2 - Squamous cell carcinoma of the head and neck (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.
AB - Squamous cell carcinoma of the head and neck (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.
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U2 - 10.1038/ncomms5527
DO - 10.1038/ncomms5527
M3 - Article
C2 - 25078033
AN - SCOPUS:84905460114
VL - 5
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 4527
ER -