MCL1 and DEDD promote urothelial carcinoma progression.

Hong AL, Guerriero JL, Doshi MB, Kynnap BD, Kim WJ, Schinzel AC, Modiste R, Schlauch AJ, Adam RM, Kwiatkowski DJ, Beroukhim R, Letai A, Rosenberg JE, Hahn WC

Molecular Cancer Research

February 18, 2019

Focal amplification of chromosome 1q23.3 in patients with advanced primary or relapsed urothelial carcinomas (UC) is associated with poor survival. We interrogated chromosome 1q23.3 and the nearby focal amplicon 1q21.3, as both are associated with increased lymph node disease in UC patients. Specifically, we assessed whether the oncogene MCL1 that resides in 1q21.3 and the genes that reside in the 1q23.3 amplicon were required for the proliferation or survival of UC. We observed that suppressing MCL1 or the Death effector domain-containing protein (DEDD) in cells that harbor amplifications of 1q21.3 or 1q23.3, respectively, inhibited cell proliferation. We also found that overexpression of MCL1 or DEDD increased anchorage independence growth in vitro and increased experimental metastasis in vivo in the non-amplified UC cell line, RT112. Expression of MCL1 confers resistance to a range of apoptosis inducers while expression of DEDD led to resistance to TNFα-induced apoptosis. These observations identify MCL1 and DEDD as genes that contribute to aggressive UC. Implications: These studies identify MCL1 and DEDD as genes that contribute to aggressive urothelial carcinomas.

Last updated: March 01, 2019