New Insight into the Significance of KLF4 PARylation in Genome Stability, Carcinogenesis, and Therapy

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2020 Nov 24

PMID 33231937

Citations 12

Authors

Zhuan Zhou

Furong Huang

Indira Shrivastava

Rui Zhu

Aiping Luo

Michael Hottiger

Ivet Bahar

Zhihua Liu

Massimo Cristofanilli

Yong Wan

Affiliations

Soon will be listed here.

Abstract

KLF4 plays a critical role in determining cell fate responding to various stresses or oncogenic signaling. Here, we demonstrated that KLF4 is tightly regulated by poly(ADP-ribosyl)ation (PARylation). We revealed the subcellular compartmentation for KLF4 is orchestrated by PARP1-mediated PARylation. We identified that PARylation of KLF4 is critical to govern KLF4 transcriptional activity through recruiting KLF4 from soluble nucleus to the chromatin. We mapped molecular motifs on KLF4 and PARP1 that facilitate their interaction and unveiled the pivotal role of the PBZ domain YYR motif (Y430, Y451 and R452) on KLF4 in enabling PARP1-mediated PARylation of KLF4. Disruption of KLF4 PARylation results in failure in DNA damage response. Depletion of KLF4 by RNA interference or interference with PARP1 function by KLF4 (a PARylation-deficient mutant) significantly sensitizes breast cancer cells to PARP inhibitors. We further demonstrated the role of KLF4 in modulating homologous recombination through regulating BRCA1 transcription. Our work points to the synergism between KLF4 and PARP1 in tumorigenesis and cancer therapy, which provides a potential new therapeutic strategy for killing BRCA1-proficient triple-negative breast cancer cells.

Citing Articles

Poly (ADP-Ribose) Polymerase Inhibitor Olaparib-Resistant -Mutant Ovarian Cancer Cells Demonstrate Differential Sensitivity to PARP Inhibitor Rechallenge.

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KLF4 interacts with TXNIP to modulate the pyroptosis in ulcerative colitis via regulating NLRP3 signaling.

Chen Y, Sun L, Liu H, Li J, Guo L, Wang Z Immun Inflamm Dis. 2024; 12(2):e1199.

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The residual cancer burden index as a valid prognostic indicator in breast cancer after neoadjuvant chemotherapy.

Xu X, Zhao W, Liu C, Gao Y, Chen D, Wu M BMC Cancer. 2024; 24(1):13.

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Human PARP1 substrates and regulators of its catalytic activity: An updated overview.

Zhu T, Zheng J, Huang L, Wang Y, Yao D, Dai H Front Pharmacol. 2023; 14:1137151.

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New insights into KLFs and SOXs in cancer pathogenesis, stemness, and therapy.

Zeng L, Zhu Y, Moreno C, Wan Y Semin Cancer Biol. 2023; 90:29-44.

PMID: 36806560 PMC: 10023514. DOI: 10.1016/j.semcancer.2023.02.003.

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