KLHL5 knockdown increases cellular sensitivity to anticancer drugs

Robert J. Schleifer, Shuchun Li, Wyatt Nechtman, Eric Miller, Shan Bai, Ashok Kumar Sharma, Jin-Xiong She

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)37429-37438
Number of pages10
JournalOncotarget
Volume9
Issue number100
StatePublished - Dec 1 2018

Fingerprint

Pharmaceutical Preparations
Neoplasms
Cell Cycle
Aurora Kinases
Cullin Proteins
Ubiquitin-Protein Ligases
Atlases
Neoplasm Genes
Ubiquitination
Phosphatidylinositol 3-Kinases
Genes
Cell Survival
Genome
Carcinoma
Kidney
Therapeutics

Keywords

  • Cell cycle
  • Combined therapy
  • KLHL
  • KLHL5
  • Synergistic effects

ASJC Scopus subject areas

  • Oncology

Cite this

Schleifer, R. J., Li, S., Nechtman, W., Miller, E., Bai, S., Sharma, A. K., & She, J-X. (2018). KLHL5 knockdown increases cellular sensitivity to anticancer drugs. Oncotarget, 9(100), 37429-37438.

KLHL5 knockdown increases cellular sensitivity to anticancer drugs. / Schleifer, Robert J.; Li, Shuchun; Nechtman, Wyatt; Miller, Eric; Bai, Shan; Sharma, Ashok Kumar; She, Jin-Xiong.

In: Oncotarget, Vol. 9, No. 100, 01.12.2018, p. 37429-37438.

Research output: Contribution to journalArticle

Schleifer, RJ, Li, S, Nechtman, W, Miller, E, Bai, S, Sharma, AK & She, J-X 2018, 'KLHL5 knockdown increases cellular sensitivity to anticancer drugs', Oncotarget, vol. 9, no. 100, pp. 37429-37438.
Schleifer RJ, Li S, Nechtman W, Miller E, Bai S, Sharma AK et al. KLHL5 knockdown increases cellular sensitivity to anticancer drugs. Oncotarget. 2018 Dec 1;9(100):37429-37438.
Schleifer, Robert J. ; Li, Shuchun ; Nechtman, Wyatt ; Miller, Eric ; Bai, Shan ; Sharma, Ashok Kumar ; She, Jin-Xiong. / KLHL5 knockdown increases cellular sensitivity to anticancer drugs. In: Oncotarget. 2018 ; Vol. 9, No. 100. pp. 37429-37438.
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