ACTL6A Induces Cisplatin Resistance in the Lung Adenocarcinoma by Inhibiting the Hippo/YAP Signaling Pathway
TANG Yan, XIE Xue-Qin, HUANG Jiu-Hong, YANG Dong-Lin, HU Chun-Sheng*
College of Pharmacy (International Academy of Targeted Therapeutics and Innovation), Chongqing University of Arts and Sciences, Chongqing 402160, China
Abstract：Actin-like 6A (ACTL6A), also known as BAF53A, is an SWI/SNF subunit of chromatin-remodeling factors and plays an important role in regulating stem cell function. Recent studies found that ACTL6A was involved in tumor occurrence and development. However, the mechanism of ACTL6A in cisplatin resistance is still unclear. This study investigated the biological function and molecular mechanism of ACTL6A in maintaining cancer stem cell function and cisplatin resistance. First, analysis from TCGA, GEO, and GEPIA databases showed that ACTL6A expression levels in lung adenocarcinoma (LUAD) tissues and cisplatin resistant cells were dramatically higher than that in adjacent normal tissues and cisplatin sensitive cells (P＜0.05), and ACTL6A high expression was positively associated with a poor prognosis of LUAD. Knockdown of ACTL6A enhanced cisplatin sensitivity (P＜0.05), reduced tumor sphere (P＜0.05), inhibited cell migration (P＜0.05), and promoted cell apoptosis (P＜0.05) in A549 cells. Western blotting showed that knockdown of ACTL6A increased the protein expression of E-cadherin, and decreased the protein expression of N-cadherin, vimentin, and twist. Moreover, knockdown of ACTL6A inhibited the expression of cancer stem cell markers, including ALDH3A1, ALDH4A1, SOX2, OCT4, and Nanog. Subsequently, Hippo/YAP signaling-related proteins were analyzed by Western blotting. The results showed the expression of beta-TRCP and YAP was decreased in A549 cell with knockdown of ACTL6A. However, phosphorylation levels at S127 and S397 of YAP were increased and inhibited translocation of YAP into the nucleus for regulating related gene expression. In summary, ACTL6A maintained the stemness of lung cancer stem cells and promoted cisplatin resistance in A549 cells by inhibiting activation of the Hippo signaling pathway.
唐艳, 谢学琴, 黄玖红, 杨东林, 胡春生. 肌动蛋白样6A抑制Hippo/YAP信号通路促进肺腺癌细胞对顺铂的耐受[J]. 中国生物化学与分子生物学报, 2021, 37(10): 1336-1344.
TANG Yan, XIE Xue-Qin, HUANG Jiu-Hong, YANG Dong-Lin, HU Chun-Sheng. ACTL6A Induces Cisplatin Resistance in the Lung Adenocarcinoma by Inhibiting the Hippo/YAP Signaling Pathway. Chinese Journal of Biochemistry and Molecular Biol, 2021, 37(10): 1336-1344.
[1] Wang R, Yamada T, Kita K, et al. Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer[J]. Nat Commun, 2020, 11(1): 4607 [2] Denisenko TV, Budkevich IN, Zhivotovsky B. Cell death-based treatment of lung adenocarcinoma[J]. Cell Death Dis, 2018, 9(2): 117 [3] Wang W, Zhao M, Cui L, et al. Characterization of a novel HDAC/RXR/HtrA1 signaling axis as a novel target to overcome cisplatin resistance in human non-small cell lung cancer[J]. Mol Cancer, 2020, 19(1): 134 [4] Shapiro G I, Wesolowski R, Devoe C, et al. Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours[J]. Br J Cancer, 2021, doi:10.1038/s41416-021-w. Online ahead of print [5] Sima X, He J, Peng J, et al. The genetic alteration spectrum of the SWI/SNF complex: The oncogenic roles of BRD9 and ACTL6A[J]. PLoS One, 2019, 14(9): e0222305 [6] Cui P, Zhang P, Zhang Y, et al. HIF-1alpha/Actl6a/H3K9ac axis is critical for pluripotency and lineage differentiation of human induced pluripotent stem cells[J]. FASEB J, 2020, 34(4): 5740-5753 [7] Zhang J, Zhang J, Wei Y, et al. ACTL6A regulates follicle-stimulating hormone-driven glycolysis in ovarian cancer cells via PGK1[J]. Cell Death Dis, 2019, 10(11): 811-824 [8] Saladi S V, Ross K, Karaayvaz M, et al. ACTL6A is co-amplified with p63 in squamous cell carcinoma to drive YAP activation, regenerative proliferation, and poor prognosis[J]. Cancer Cell, 2017, 31(1): 35-49 [9] Xiao Y, Lin FT, Lin WC. ACTL6A promotes repair of cisplatin-induced DNA damage, a new mechanism of platinum resistance in cancer[J]. Proc Natl Acad Sci USA, 2021, 118(3): e2015808118 [10] Sun W, Wang W, Lei J, et al. Actin-like protein 6A is a novel prognostic indicator promoting invasion and metastasis in osteosarcoma[J]. Oncol Rep, 2017, 37(4): 2405-2417 [11] Galluzzi L, Senovilla L, Vitale I, et al. Molecular mechanisms of cisplatin resistance[J]. Oncogene, 2012, 31(15): 1869-1883 [12] Shen L, Xia M, Zhang Y, et al. Mitochondrial integration and ovarian cancer chemotherapy resistance[J]. Exp Cell Res, 2021, 401(2): 112549 [13] Carotenuto P, Hedayat S, Fassan M, et al. Modulation of biliary cancer chemo-resistance through microRNA-mediated rewiring of the expansion of CD133+ cells[J]. Hepatology, 2020, 72(3): 982-996 [14] Ji J, Xu R, Zhang X, et al. Actin like-6A promotes glioma progression through stabilization of transcriptional regulators YAP/TAZ[J]. Cell Death Dis, 2018, 9(5): 517 [15] Wu JI. Diverse functions of ATP-dependent chromatin remodeling complexes in development and cancer[J]. Acta Biochim Biophys(Shanghai) Sin, 2012, 44(1): 54-69 [16] Krasteva V, Buscarlet M, Diaz-Tellez A, et al. The BAF53a subunit of SWI/SNF-like BAF complexes is essential for hemopoietic stem cell function[J]. Blood, 2012, 120(24): 4720-4732 [17] Xiao S, Chang RM, Yang MY, et al. Actin-like 6A predicts poor prognosis of hepatocellular carcinoma and promotes metastasis and epithelial-mesenchymal transition[J]. Hepatology, 2016, 63(4): 1256-1271 [18] 孟辉, 郭正阳, 张腾瑞, 等. 非诺贝特通过激活Hippo信号通路抑制肿瘤细胞的增殖[J]. 中国生物化学与分子生物学报 (Meng H, Guo ZY, Zhang TR, et al. Fenofibrate inhibits proliferation of cancer cells by activating Hippo signaling pathway[J]. Chin J Biochem Mol Biol), 2020, 36(6): 674-679 [19] Park J H, Shin JE, Park HW. The role of Hippo pathway in cancer stem cell biology[J]. Mol Cells, 2018, 41(2): 83-92 [20] Cheung P, Xiol J, Dill MT, et al. Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer[J]. Cell Stem Cell, 2020, 27(4): 590-604.e9
