Schleifer Robert J, Li Shuchun, Nechtman Wyatt, Miller Eric, Bai Shan, Sharma Ashok, She Jin-Xiong
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Oncotarget. 2018 Dec 21;9(100):37429-37438. doi: 10.18632/oncotarget.26462.
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, , with the pharmacologic effect of anti-cancer drugs. 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 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 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.
KLHL家族基因因其通过与Cullin-3（CUL3）结合参与E3连接酶泛素化途径而闻名，这会导致特定结合伴侣的降解。因此，KLHL基因在癌症研究中备受关注，因为它们可以直接影响与治疗相关的细胞周期调节因子的降解，如极光激酶、PLK1或CDK1。然而，大多数KLHL家族成员在文献中仍未得到充分研究。本研究探讨了KLHL成员的表达与抗癌药物药理作用之间的关系。敲低KLHL成员可降低癌细胞的增殖和活力，并使癌细胞对多种抗癌药物敏感。与细胞周期相关的药物，包括Akt/PI3K/mTOR抑制剂，在敲低KLHL成员后尤其敏感。通过对癌症基因组图谱（TCGA）肿瘤组进行泛癌研究，将KLHL5作为癌症预后或诊断标志物的潜力与其他KLHL进行了比较。虽然KLHL5在癌症中的表达显示出轻微失调，但其他KLHL在所有癌症类型中均表现出显著失调，在肾癌中尤为明显。本研究主张进一步研究KLHL作为潜在的替代治疗靶点，因为虽然KLHL5是一个影响抗癌药物效果的新基因，但其他KLHL可能对药物效果有类似影响，同时作为诊断或预后标志物具有更大的潜力。
