KIF3A binds to β-arrestin for suppressing Wnt/β-catenin signalling independently of primary cilia in lung cancer.
Aberrant Wnt/β-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/β-catenin signalling in NSCLC cells. KIF3A knockdown increases both β-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds β-arrestin, KIF3A depletion allows β-arrestin to form a complex with DVL2 and axin, stabilizing β-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase β-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as β-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/β-catenin signalling and tumourigenesis in NSCLC.
Biomedical science and engineering interdisciplinary program, KAIST, Daejeon, South Korea.|Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Minsuh
M
Kim
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Young-Ah
YA
Suh
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Ju-Hee
JH
Oh
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Bo Ra
BR
Lee
Biomedical science and engineering interdisciplinary program, KAIST, Daejeon, South Korea.|Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea.
Joon
J
Kim
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.|Asan Center for Cancer Genome Discovery, Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Se Jin
SJ
Jang
D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002923:Cilia / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D060490:Receptors, Wnt / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*; D000071557:beta-Arrestins / Q000378:metabolism*
C495270:CTNNB1 protein, human; C087415:KIF3A protein, human; D060490:Receptors, Wnt; D051176:beta Catenin; D000071557:beta-Arrestins; D016547:Kinesins