KLHL family genes are noted for their involvement in the E3 ligase ubiquitination pathway through binding with Cullin-3 (CUL3) resulting in degradation of specific binding partners. KLHLs are thus intriguing genes for cancer as they can directly influence the degradation of therapeutically relevant cell cycle regulators such as Aurora Kinase, PLK1, or CDK1. However, most KLHL family members remain understudied within the literature. This study explores the relationship of expression of KLHL member, KLHL5, with the pharmacologic effect of anti-cancer drugs. KLHL5 knockdown decreased the proliferation and viability of cancer cells and sensitized cancer cells to numerous anti-cancer drugs. Drugs related to cell cycle including Akt/PI3K/mTOR inhibitors were especially sensitized by KLHL5 knockdown. The potential of KLHL5 as a prognostic or diagnostic cancer marker was compared to other KLHLs through a pan-cancer study of The Cancer Genome Atlas (TCGA) tumor groups. While KLHL5 expression shows marginal dysregulation in cancer, other KLHLs exhibit significant dysregulation in all cancer types, and exceptionally in renal carcinomas. This study advocates for further study of KLHLs as potential alternative therapeutic targets, since while KLHL5 is a novel gene impacting anticancer drug effects, others may have a similar impact on drug effect while having greater potential as diagnostic or prognostic markers.
Keywords: KLHL; KLHL5; cell cycle; combined therapy; synergistic effects.