Identification of cofilin-1 as a novel mediator for the metastatic potentials and chemoresistance of the prostate cancer cells

Genome-wide association studies (GWAS) have identified >200 loci associated with breast cancer (BC) risk. The majority of candidate causal variants (CCVs) are in non-coding regions and likely modulate cancer risk by regulating gene expression. However, pinpointing the exact target of the association and identifying the phenotype it mediates is a major challenge in the interpretation and translation of GWAS. Here, we used pooled CRISPR activation and suppression screens to evaluate predicted GWAS target genes, and to define the cancer phenotypes they mediate. We measured proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We performed 60 CRISPR screens and identified 21 genes predicted with high confidence to be GWAS targets that drive a cancer phenotype by driving a proliferation or DNA damage response in breast cells. We validated the regulation of a subset of these genes by BC-risk variants, and show the utility of expression profiling for drug repurposing. We provide a platform for identifying gene targets of risk variants, and present a blueprint of interventions for BC risk reduction and treatment.

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“…5D). This is consistent with the known function of CFL1 as a regulator of actin filament polymerization and cell motility 24,25 .…”

Section: Bc Risk Genes That Induce a Proliferation Phenotype In 2d And 3d Culturessupporting

confidence: 90%

CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci

Rosenbluh

Tuano

Milne

et al. 2022

Preprint

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“…2F). This is consistent with the known function of CFL1 as a regulator of actin filament polymerization and cell motility (Chen et al, 2020;Li et al, 2021).…”

Section: Bc Associated Risk Genes That Upon Suppression or Overexpression Induce Cell Proliferation Phenotype In 2d And 3d Culturessupporting

confidence: 87%

CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci

Tuano

Beesley

Manning

et al. 2021

Preprint

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Genome-wide association studies (GWAS) have identified >200 loci associated with breast cancer (BC) risk. The majority of candidate causal variants (CCVs) are in non-coding regions and are likely to modulate cancer risk by regulating gene expression. We recently developed a scoring system, INQUISIT, to predict candidate risk genes at BC-risk loci. Here, we used pooled CRISPR activation and suppression screens to validate INQUISIT predictions, and to define the cancer phenotypes they mediate. We measured proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on the DNA damage response. We performed 60 CRISPR screens and identified 21 high-confidence INQUISIT predictions that mediate a cancer phenotype. We validated the direct regulation of a subset of genes by BC-risk variants using HiCHIP and CRISPRqtl. Furthermore, we show the utility of expression profiling for drug repurposing against these targets. We provide a platform for identifying gene targets of risk variants, and lay a blueprint of interventions for BC risk reduction and treatment.

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“…We also uncovered a novel relationship between BAIAP2L1 and cofilin, a key protein that initiates early steps in the motility cycle. Similar to that of BAIAP2L1, misregulations of the cofilin pathway have been recently documented in invasive cancer [8]. Upregulations of cofilin or phospho-Ser3-cofilin, without any control for the distribution, disrupted the cell migration rather than promoted it [9][10][11].…”

mentioning

confidence: 82%

BAIAP2L1 enables cancer cell migration and facilitates phospho‐Cofilin asymmetry localization in the border cells

Pipatpanyanugoon

Wareesawetsuwan

Prasopporn

et al. 2021

Cancer Communications

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Dear Editor,Cancer invasion and metastasis are among the most clinically relevant cancer hallmarks. Identification of molecular pathways that contribute to cancer cell motility a crucial step in cancer invasion/metastasis is essential to understanding how cancer motility is regulated and may provide therapeutic targets for treating metastatic cancer. Brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (BAIAP2L1) is a novel oncoprotein whose high-leveled expressions have been correlated with advanced and metastatic stages of cancer [1-3]. We have previously uncovered BAIAP2L1 as a novel oncogene by integrative analysis of protein-protein interactome and somatic copy number alterations in human cancers [4]. Although in vivo xenograft model showed that BAIAP2L1 promoted tumor growth [4], however, the exact mechanism by which BAIAP2L1 facilitates tumorigenesis remains unclear.We hypothesized that expressions of BAIAP2L1 were involved with metastatic/invasive phenotypes of cancer. To investigate, we selected the breast cancer cell line MCF7 which expressed an acceptable level of BAIAP2L1 mRNA (Supplementary Fig. S1). Detailed methods can be found in the Supplementary File. We depleted endogenous BAIAP2L1 in MCF7 by BAIAP2L1-specific shorthairpin RNAs (shRNAs) and measured cancer cell migration via wound-healing assay. We found that BAIAP2L1-

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Identification of cofilin-1 as a novel mediator for the metastatic potentials and chemoresistance of the prostate cancer cells

Cited by 18 publications

References 47 publications

CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci

CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci

CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci

BAIAP2L1 enables cancer cell migration and facilitates phospho‐Cofilin asymmetry localization in the border cells

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