Abstract
Tumors that overexpress the MYC oncogene are frequently aneuploid, a state associated with highly aggressive cancers and tumor evolution. However, how MYC causes aneuploidy is not well understood. Here, we show that MYC overexpression induces mitotic spindle assembly defects and chromosomal instability (CIN) through effects on microtubule nucleation and organization. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, indicating an ongoing role for MYC in CIN. MYC reprograms mitotic gene expression, and we identify TPX2 to be permissive for spindle assembly in MYC-high cells. TPX2 depletion blocks mitotic progression, induces cell death, and prevents tumor growth. Further elevating TPX2 expression reduces mitotic defects in MYC-high cells. MYC and TPX2 expression may be useful biomarkers to stratify patients for anti-mitotic therapies. Our studies implicate MYC as a regulator of mitosis and suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.
Highlights
Aneuploidy, a state of abnormal chromosome number, is a hallmark of cancer, with >70% of common solid tumors found to be aneuploid (Boveri, 2008; Cimini, 2008)
Tumors that overexpress the MYC oncogene are frequently aneuploid, a state associated with highly aggressive cancers and tumor evolution
We show that MYC overexpression induces mitotic spindle assembly defects and chromosomal instability (CIN) through effects on microtubule nucleation and organization
Summary
Aneuploidy, a state of abnormal chromosome number, is a hallmark of cancer, with >70% of common solid tumors found to be aneuploid (Boveri, 2008; Cimini, 2008). The MYC oncogene is frequently overexpressed in a wide variety of aggressive and metastatic tumors and has been associated with aneuploidy (Felsher and Bishop, 1999a; Karlsson et al, 2003; McCormack et al, 1998; Soucek and Evan, 2010). One of the key biological functions of MYC is its ability to facilitate entry and progression through G1 and S phases of the cell cycle by regulating gene transcription (Bretones et al, 2015). Whether MYC affects mitotic progression and induces CIN is unclear. A molecular mechanism for the synthetic-lethal interactions of MYC with mitotic regulators is missing. Clarifying such a mechanism could reveal novel treatment strategies for aggressive MYC-overexpressing cancers
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