RT Journal Article
SR Electronic
T1 MYC Dysregulates Mitotic Spindle Function Creating a Dependency on TPX2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 272336
DO 10.1101/272336
A1 Julia Rohrberg
A1 Alexandra Corella
A1 Moufida Taileb
A1 Seda Kilinc
A1 Marie-Lena Jokisch
A1 Roman Camarda
A1 Alicia Zhou
A1 Sanjeev Balakrishnan
A1 Aaron N. Chang
A1 Andrei Goga
YR 2018
UL http://biorxiv.org/content/early/2018/04/05/272336.abstract
AB The MYC oncogene promotes tumorigenesis in part by facilitating cell cycle entry thus driving cellular proliferation. Tumors that overexpress MYC frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. While the role of MYC in overcoming the G1/S checkpoint is well established, it remains poorly understood whether MYC induces chromosomal instability (CIN). Here, we identify a direct influence of MYC on mitotic progression. MYC overexpression induces defects in microtubule nucleation and spindle assembly promoting chromosome segregation defects, micronuclei and CIN. We examined which mitotic regulators are required for the survival of MYC-overexpressing cells and found a reliance on high TPX2 expression. TPX2, a master microtubule regulator, is overexpressed together with MYC in multiple cell lines, in mouse tumor models and in aggressive human breast cancers. High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with deregulated MYC, whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Importantly, attenuation of MYC expression reverses the mitotic defects observed, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of a CIN phenotype in tumors. Here, we implicate the MYC oncogene as a regulator of spindle assembly and dynamics and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.