FERM domain-containing protein FRMD6 activates the mTOR signaling pathway and promotes lung cancer progression
Tianzhuo Wang, Huiying Guo, Lei Zhang, Miao Yu, Qianchen Li, Jing Zhang, Yan Tang, Hongquan Zhang, Jun Zhan()
Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences; Peking University International Cancer Institute; MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China
FRMD6, a member of the 4.1 ezrin–radixin–moesin domain-containing protein family, has been reported to inhibit tumor progression in multiple cancers. Here, we demonstrate the involvement of FRMD6 in lung cancer progression. We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues. In addition, the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma (n = 75, P = 0.0054) and lung adenocarcinoma (n = 94, P = 0.0330). Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6. Mechanistically, FRMD6 interacts and colocalizes with mTOR and S6K, which are the key molecules of the mTOR signaling pathway. FRMD6 markedly enhances the interaction between mTOR and S6K, subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells. Furthermore, knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6−/− gene KO MEFs and mice. Altogether, our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.
. [J]. Frontiers of Medicine, 2023, 17(4): 714-728.
Tianzhuo Wang, Huiying Guo, Lei Zhang, Miao Yu, Qianchen Li, Jing Zhang, Yan Tang, Hongquan Zhang, Jun Zhan. FERM domain-containing protein FRMD6 activates the mTOR signaling pathway and promotes lung cancer progression. Front. Med., 2023, 17(4): 714-728.
J Didkowska, U Wojciechowska, M Mańczuk, J Łobaszewski. Lung cancer epidemiology: contemporary and future challenges worldwide. Ann Transl Med 2016; 4(8): 150 https://doi.org/10.21037/atm.2016.03.11
pmid: 27195268
2
H Sung, J Ferlay, RL Siegel, M Laversanne, I Soerjomataram, A Jemal, F Bray. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209–249 https://doi.org/10.3322/caac.21660
pmid: 33538338
3
K Wadowska, I Bil-Lula, Ł Trembecki, M Śliwińska-Mossoń. Genetic markers in lung cancer diagnosis: a review. Int J Mol Sci 2020; 21(13): E4569 https://doi.org/10.3390/ijms21134569
pmid: 32604993
NM Kronenberg, A Tilston-Lunel, FE Thompson, D Chen, W Yu, K Dholakia, MC Gather, FJ Gunn-Moore. Willin/FRMD6 influences mechanical phenotype and neuronal differentiation in mammalian cells by regulating ERK1/2 activity. Front Cell Neurosci 2020; 14: 552213 https://doi.org/10.3389/fncel.2020.552213
pmid: 33088261
9
J Haldrup, SH Strand, C Cieza-Borrella, ME Jakobsson, M Riedel, M Norgaard, S Hedensted, F Dagnaes-Hansen, BP Ulhoi, R Eeles, M Borre, JV Olsen, M Thomsen, Z Kote-Jarai, KD Sorensen. FRMD6 has tumor suppressor functions in prostate cancer. Oncogene 2021; 40(4): 763–776 https://doi.org/10.1038/s41388-020-01548-w
pmid: 33249427
10
D Chen, W Yu, L Aitken, F Gunn-Moore. Willin/FRMD6: a multi-functional neuronal protein associated with Alzheimer’s disease. Cells 2021; 10(11): 3024 https://doi.org/10.3390/cells10113024
pmid: 34831245
11
J Beck, M Kressel. FERM domain-containing protein 6 identifies a subpopulation of varicose nerve fibers in different vertebrate species. Cell Tissue Res 2020; 381(1): 13–24 https://doi.org/10.1007/s00441-020-03189-7
pmid: 32200438
12
L Angus, S Moleirinho, L Herron, A Sinha, X Zhang, M Niestrata, K Dholakia, MB Prystowsky, KF Harvey, PA Reynolds, FJ Gunn-Moore. Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP. Oncogene 2012; 31(2): 238–250 https://doi.org/10.1038/onc.2011.224
pmid: 21666719
13
LE Fodor, A Gézsi, L Ungvári, AF Semsei, Z Gál, A Nagy, G Gálffy, L Tamási, A Kiss, P Antal, C Szalai. Investigation of the possible role of the Hippo/YAP1 pathway in asthma and allergy. Allergy Asthma Immunol Res 2017; 9(3): 247–256 https://doi.org/10.4168/aair.2017.9.3.247
pmid: 28293931
14
S Moleirinho, C Patrick, AM Tilston-Lünel, JR Higginson, L Angus, M Antkowiak, SC Barnett, MB Prystowsky, PA Reynolds, FJ Gunn-Moore. Willin, an upstream component of the Hippo signaling pathway, orchestrates mammalian peripheral nerve fibroblasts. PLoS One 2013; 8(4): e60028 https://doi.org/10.1371/journal.pone.0060028
pmid: 23593160
15
S Visser-Grieve, Y Hao, X Yang. Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway. Oncogene 2012; 31(9): 1189–1195 https://doi.org/10.1038/onc.2011.318
pmid: 21785462
16
Y Xu, K Wang, Q Yu. FRMD6 inhibits human glioblastoma growth and progression by negatively regulating activity of receptor tyrosine kinases. Oncotarget 2016; 7(43): 70080–70091 https://doi.org/10.18632/oncotarget.12148
pmid: 27661120
17
MK Holz, BA Ballif, SP Gygi, J Blenis. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005; 123(4): 569–580 https://doi.org/10.1016/j.cell.2005.10.024
pmid: 16286006
18
M Murakami, T Ichisaka, M Maeda, N Oshiro, K Hara, F Edenhofer, H Kiyama, K Yonezawa, S Yamanaka. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004; 24(15): 6710–6718 https://doi.org/10.1128/MCB.24.15.6710-6718.2004
pmid: 15254238
19
YG Gangloff, M Mueller, SG Dann, P Svoboda, M Sticker, JF Spetz, SH Um, EJ Brown, S Cereghini, G Thomas, SC Kozma. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 2004; 24(21): 9508–9516 https://doi.org/10.1128/MCB.24.21.9508-9516.2004
pmid: 15485918
20
Y Dobashi, S Suzuki, H Matsubara, M Kimura, S Endo, A Ooi. Critical and diverse involvement of Akt/mammalian target of rapamycin signaling in human lung carcinomas. Cancer 2009; 115(1): 107–118 https://doi.org/10.1002/cncr.23996
pmid: 19090006
21
Y Dobashi, S Suzuki, M Kimura, H Matsubara, H Tsubochi, I Imoto, A Ooi. Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human lung carcinomas. Hum Pathol 2011; 42(2): 214–226 https://doi.org/10.1016/j.humpath.2010.05.025
pmid: 21040950
22
M Hiramatsu, H Ninomiya, K Inamura, K Nomura, K Takeuchi, Y Satoh, S Okumura, K Nakagawa, T Yamori, M Matsuura, T Morikawa, Y Ishikawa. Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations. Lung Cancer 2010; 70(1): 94–102 https://doi.org/10.1016/j.lungcan.2010.01.001
pmid: 20117855
23
Y Dobashi, Y Watanabe, C Miwa, S Suzuki, S Koyama. Mammalian target of rapamycin: a central node of complex signaling cascades. Int J Clin Exp Pathol 2011; 4(5): 476–495
pmid: 21738819
J Song, T Wang, X Chi, X Wei, S Xu, M Yu, H He, J Ma, X Li, J Du, X Sun, Y Wang, J Zhan, H Zhang. Kindlin-2 inhibits the Hippo signaling pathway by promoting degradation of MOB1. Cell Rep 2019; 29(11): 3664–3677.e5 https://doi.org/10.1016/j.celrep.2019.11.035
pmid: 31825843
J Zhan, P Wang, S Li, J Song, H He, Y Wang, Z Liu, F Wang, H Bai, W Fang, Q Du, M Ye, Z Chang, J Wang, H Zhang. HOXB13 networking with ABCG1/EZH2/Slug mediates metastasis and confers resistance to cisplatin in lung adenocarcinoma patients. Theranostics 2019; 9(7): 2084–2099 https://doi.org/10.7150/thno.29463
pmid: 31037158
29
J Wan, J Zhan, S Li, J Ma, W Xu, C Liu, X Xue, Y Xie, W Fang, YE Chin, H Zhang. PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progression. Nucleic Acids Res 2015; 43(7): 3591–3604 https://doi.org/10.1093/nar/gkv238
pmid: 25800736
30
J Song, T Wang, W Xu, P Wang, J Wan, Y Wang, J Zhan, H Zhang. HOXB9 acetylation at K27 is responsible for its suppression of colon cancer progression. Cancer Lett 2018; 426: 63–72 https://doi.org/10.1016/j.canlet.2018.04.002
pmid: 29654889
31
A González, MN Hall, SC Lin, DG Hardie. AMPK and TOR: the yin and yang of cellular nutrient sensing and growth control. Cell Metab 2020; 31(3): 472–492 https://doi.org/10.1016/j.cmet.2020.01.015
pmid: 32130880
32
CS Zhang, B Jiang, M Li, M Zhu, Y Peng, YL Zhang, YQ Wu, TY Li, Y Liang, Z Lu, G Lian, Q Liu, H Guo, Z Yin, Z Ye, J Han, JW Wu, H Yin, SY Lin, SC Lin. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab 2014; 20(3): 526–540 https://doi.org/10.1016/j.cmet.2014.06.014
pmid: 25002183
33
C Guan, Z Chang, X Gu, R Liu. MTA2 promotes HCC progression through repressing FRMD6, a key upstream component of Hippo signaling pathway. Biochem Biophys Res Commun 2019; 515(1): 112–118 https://doi.org/10.1016/j.bbrc.2019.05.025
pmid: 31128910
