Targeting LDHC dysregulates the cell cycle and improves sensitivity to cisplatin and olaparib

Abstract

The cancer testis antigen (CTA) lactate dehydrogenase C (LDHC) is a promising anti-cancer target with tumor-specific expression, immunogenicity and a role in metabolic reprogramming. Interrogation of the TCGA breast cancer cohort demonstrates upregulation of LDHC expression, conferring unfavorable prognosis. Although the role of LDHC is well characterized in spermatocytes, its role in tumors remains largely unknown. We investigated whether LDHC is involved in regulating genomic stability and may be targeted to affect tumor cellular fitness. Silencing LDHC in four breast cancer cell lines significantly increased the presence of giant cells and nuclear aberrations, DNA damage and apoptosis. LDHC silenced cells demonstrated aberrant cell cycle progression with differential expression of cell cycle checkpoint and DNA damage response regulators. In addition, LDHC silencing induced microtubule destabilization, culminating in increased mitotic catastrophe and reduced long-term survival. Notably, cisplatin and olaparib treatment further reduced survival of LDHC silenced cells. This study supports the therapeutic potential of targeting LDHC to mitigate cancer cell survival, and improve sensitivity to DNA damaging and DNA damage repair inhibiting agents.