Epithelial protein lost in neoplasm (EPLIN): Beyond a tumor suppressor

Abstract

The majority of cancer-related deaths are caused by tumor recurrence, metastasis and therapeutic resistance. During the late stages of tumor progression, multiple factors are involved, including the downregulation and/or loss of function of metastasis suppressors. Epithelial protein lost in neoplasm (EPLIN), an actin-binding protein, was initially identified as a putative tumor suppressor that is frequently downregulated in epithelial tumors. Recent evidence indicates that EPLIN may negatively regulate epithelia-to-mesenchymal transition (EMT), a crucial process by which cancer cells acquire invasive capabilities and therapeutic resistance. Importantly, downregulation of EPLIN is associated with clinical metastasis in a variety of solid tumors, suggesting that EPLIN could be a suppressor of metastasis. In this review, I will discuss the regulation and function of EPLIN in human cancer cells and explore the clinical significance of EPLIN in metastatic disease.

Keywords: Actin cytoskeleton; Chemoresistance; EPLIN; Epithelial-to-mesenchymal transition; Metastasis suppressor; Tumor suppressor.

Fig. 1

(A) The genomic and protein structures of human EPLIN isoforms. (B) Three-dimensional structure of LIM domain of human EPLIN (PDB ID = 2D8Y), generated with FirstGlance in Jmol.

Fig. 2

IHC expression of EPLIN in human bladder cancer vs. normal tissues in a bladder TMA (obtained from Creative-Bioarray, New York). A & B: normal bladder tissues; C: grade 1, stage II, T2N0M0; D: grade 3, stage II, T2aN0M0.

Fig. 3

EPLIN links the cadherin-β-catenin-α-catenin complex to actin cytoskeletons, which is essential to the maintenance of apical–basal polarity in epithelial cells.

Fig. 4

Potential EPLIN-interacting proteins, predicted using STRING program. Abbreviations: ATP6V1B1: ATPase, H+ transporting, lysosomal 56/58 kDa, V1 subunit B1; BMI1: BMI1 polycomb ring finger oncogene; CDH1: cadherin 1, type 1, E-cadherin (epithelial); CTNNA1: catenin (cadherin-associated protein), alpha 1; CTNNB1: catenin (cadherin-associated protein), beta 1; CTNND1: catenin (cadherin-associated protein), delta 1; EZH2: enhancer of zeste homolog 2; FMNL1: formin-like 1; GRB2: growth factor receptor-bound protein 2; IKBKG: inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma; LIMA1: LIM domain and actin binding 1, or EPLIN; LRCH3: leucine-rich repeats and calponin homology (CH) domain containing 3; MAP3K3: mitogen-activated protein kinase kinase kinase 3; PAN2: PAN2 poly(A) specific ribonuclease subunit homolog; RIPK3: receptor-interacting serine–threonine kinase 3; RNF2: ring finger protein 2; SUZ12: suppressor of zeste 12 homolog, or Polycomb group (PcG) protein; SVIL: supervillin; TP53: tumor protein p53; UBC: ubiquitin C; UBXN6: UBX domain protein 6; YWHAB: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide; YWHAE: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide; YWHAG: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, gamma polypeptide; YWHAH: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide.