ARID1A down-regulation reduces autophagic flux in colorectal cancer: a potential candidate in cancer therapy ARID1A down-regulation impairs autophagy in CRC
Gastroenterology and Hepatology from Bed to Bench,
,
2 March 2026
,
Page 1-11 (e14)
https://doi.org/10.22037/ghfbb.v19i01.3199
Abstract
Aim: This study planned to examine the latent impacts of ARID1A in modulating autophagy in colorectal cancer (CRC), thereby providing new insights into the potential regulatory role of ARID1A in CRC.
Background: ARID1A, an essential component of the SWI/SNF complex, is considered a recognized tumor suppressor, which is frequently inactivated and down-regulated in various human cancers, including CRC. Nevertheless, its potential role in regulating cell autophagy, a crucial cellular homeostatic mechanism that plays a pro-death or pro-survival role in cancer, remained unknown in CRC.
Methods: The expression of ARID1A was evaluated using real-time quantitative PCR (qPCR) and western blotting in the HCT116 cell line. After the shRNA-mediated knockdown of ARID1A, cellular proliferation and autophagy flux were evaluated using the MTT assay, P62 and LC3Western blotting, and the LysoTracker method, respectively.
Results: Transduction of ARID1A shRNA lentivirus resulted in approximately 86 % downregulation of ARID1A mRNA expression in HCT116 cells. The MTT assay of HCT116 cells revealed approximately 1.5-fold significant increase in cell proliferation following the ARID1A down-regulation. Based on the western blot results, aggregation of p62 and LC3-II revealed autophagy flux inhibition after ARID1A down-regulation. In confirmation of this result, the LysoTracker staining showed lysosomal alkalinization, autophagosome aggregation, and inhibition of autophagic flux following ARID1A down-regulation. Therefore, enhanced autophagosome presence and impaired autophagic flux induced by ARID1A down-regulation may be at least in part as a result of lysosomal environment imbalance.
Conclusion: This study reports autophagy inactivation as the possible mechanism by which ARID1A down-regulation promotes CRC. Therefore, autophagy inducers may represent promising therapeutic targets for ARID1A-deficient tumors.
- Colorectal Neoplasms
- ARID1A
- Gene knockdown
- Autophagy
- Antineoplastic Therapy
How to Cite
References
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
2. Han Y-H, Mun J-G, Jeon HD, Kee J-Y, Hong S-H. Betulin inhibits lung metastasis by inducing cell cycle arrest, autophagy, and apoptosis of metastatic colorectal cancer cells. Nutrients 2019;12:66.
3. Chatterjee S, Sarkar S, Bhattacharya S. Toxic metals and autophagy. Chem Res Toxicol 2014;27:1887-900.
4. Zhang C, Feng X, He L, Zhang Y, Shao L. The interrupted effect of autophagic flux and lysosomal function induced by graphene oxide in p62-dependent apoptosis of F98 cells. J Nanobiotechnology 2020;18:1-17.
5. Jankó L, Sári Z, Kovács T, Kis G, Szántó M, Antal M, et al. Silencing of PARP2 blocks autophagic degradation. Cells 2020;9:380.
6. Choi KS. Autophagy and cancer. Exp Mol Med 2012;44:109-20.
7. Lauzier A, Normandeau-Guimond J, Vaillancourt-Lavigueur V, Boivin V, Charbonneau M, Rivard N, et al. Colorectal cancer cells respond differentially to autophagy inhibition in vivo. Sci Rep 2019;9:11316.
8. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012;12:401-10.
9. Sun T. Long noncoding RNAs act as regulators of autophagy in cancer. Pharmacol Res 2018;129:151-5.
10. Euskirchen G, Auerbach RK, Snyder M. SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J Biol Chem 2012;287:30897-905.
11. Shen J, Peng Y, Wei L, Zhang W, Yang L, Lan L, et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov 2015;5:752-67.
12. Mathur R. ARID1A loss in cancer: towards a mechanistic understanding. Pharmacol Ther 2018;190:15-23.
13. Mathur R, Alver BH, San Roman AK, Wilson BG, Wang X, Agoston AT, et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 2017;49:296.
14. Samartzis EP, Gutsche K, Dedes KJ, Fink D, Stucki M, Imesch P. Loss of ARID1A expression sensitizes cancer cells to PI3K-and AKT-inhibition. Oncotarget 2014;5:5295.
15. Erfani M, Zamani M, Hosseini SY, Mostafavi-Pour Z, Shafiee SM, Saeidnia M, et al. ARID1A regulates E-cadherin expression in colorectal cancer cells: a promising candidate therapeutic target. Mol Biol Rep 2021;48:6749-56.
16. Tessiri S, Techasen A, Kongpetch S, Namjan A, Loilome W, Chan-On W, et al. Therapeutic targeting of ARID1A and PI3K/AKT pathway alterations in cholangiocarcinoma. PeerJ 2022;10:e12750.
17. Mullen J, Kato S, Sicklick JK, Kurzrock R. Targeting ARID1A mutations in cancer. Cancer Treat Rev 2021;100:102287.
18. Jones S, Li M, Parsons DW, Zhang X, Wesseling J, Kristel P, et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat 2012;33:100-3.
19. Network CGA. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330.
20. Cajuso T, Hänninen UA, Kondelin J, Gylfe AE, Tanskanen T, Katainen R, et al. Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer. Int J Cancer 2014;135:611-23.
21. Erfani M, Hosseini SV, Mokhtari M, Zamani M, Tahmasebi K, Alizadeh Naini M, et al. Altered ARID1A expression in colorectal cancer. BMC Cancer 2020;20:1-13.
22. Erfani M, Zamani M, Mokarram P. Evidence of histone modification affecting ARID1A expression in colorectal cancer cell lines. Gastroenterol Hepatol Bed Bench 2022;15:32.
23. Kuroda H, Kutner RH, Bazan NG, Reiser J. Simplified lentivirus vector production in protein-free media using polyethylenimine-mediated transfection. J Virol Methods 2009;157:113-21.
24. Lai SC, Devenish RJ. LC3-associated phagocytosis (LAP): connections with host autophagy. Cells. 2012;1:396-408.
25. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 2021;17:1-382.
26. Ghavami S, Zamani M, Ahmadi M, Erfani M, Dastghaib S, Darbandi M, et al. Epigenetic regulation of autophagy in gastrointestinal cancers. Biochim Biophys Acta Mol Basis Dis 2022;1868:166512.
27. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008;132:27-42.
28. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67-93.
29. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003;112:1809-20.
30. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 2003;100:15077-82.
31. Guo W, Chen Z, Chen Z, Yu J, Liu H, Li T, et al. Promotion of cell proliferation through inhibition of cell autophagy signalling pathway by Rab3IP is restrained by microRNA-532-3p in gastric cancer. J Cancer 2018;9:4363.
32. Zhao ChuanKe ZC, She TianTian ST, Wang LiXin WL, Su YaHui SY, Qu LiKe QL, Gao YuJing GY, et al. Daucosterol inhibits cancer cell proliferation by inducing autophagy through reactive oxygen species-dependent manner. Life Sci 2015;137:37-43.
33. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672-6.
34. Ye Y, Fang Y, Xu W, Wang Q, Zhou J, Lu R. 3, 3′-Diindolylmethane induces anti-human gastric cancer cells by the miR-30e-ATG5 modulating autophagy. Biochem Pharmacol 2016;115:77-84.
35. Galluzzi L, Bravo-San Pedro JM, Demaria S, Formenti SC, Kroemer G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat Rev Clin Oncol 2017;14:247-58.
36. O’Donovan TR, Rajendran S, O’Reilly S, O’Sullivan GC, McKenna SL. Lithium modulates autophagy in esophageal and colorectal cancer cells and enhances the efficacy of therapeutic agents in vitro and in vivo. PLoS One 2015;10:e0134676.
37. Li S, Yang G, Zhu X, Cheng L, Sun Y, Zhao Z. Combination of rapamycin and garlic-derived S-allylmercaptocysteine induces colon cancer cell apoptosis and suppresses tumor growth in xenograft nude mice through autophagy/p62/Nrf2 pathway. Oncol Rep 2017;38:1637-44.
38. Ren W-W, Li D-D, Chen X, Li X-L, He Y-P, Guo L-H, et al. MicroRNA-125b reverses oxaliplatin resistance in hepatocellular carcinoma by negatively regulating EVA1A mediated autophagy. Cell Death Dis 2018;9:547.
39. Zhang Y, Li C, Liu X, Wang Y, Zhao R, Yang Y, et al. circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637. EBioMedicine 2019;48:277-88.
40. Liu X, Gomez-Pinillos A, Shah P, Lavilla C, Ferrari AC. Effect of inhibition of the PI3K/Akt/mTOR pathway on AR splicing and downstream targets. Am Soc Clin Oncol; 2013.
41. Mans LA, Querol Cano L, van Pelt J, Giardoglou P, Keune WJ, Haramis AP. The tumor suppressor LKB1 regulates starvation-induced autophagy under systemic metabolic stress. Sci Rep 2017;7:7327.
42. Wang S, Li J, Du Y, Xu Y, Wang Y, Zhang Z, et al. The Class I PI3K inhibitor S14161 induces autophagy in malignant blood cells by modulating the Beclin 1/Vps34 complex. J Pharmacol Sci 2017;134:197-202.
43. Sun D, Qian H, Wang J, Xie T, Teng F, Li J, et al. ARID1A deficiency reverses the response to anti-PD (L) 1 therapy in EGFR-mutant lung adenocarcinoma by enhancing autophagy-inhibited type I interferon production. Cell Commun Signal 2022;20:156.
44. Wu H, Lu X-X, Wang J-R, Yang T-Y, Li X-M, He X-S, et al. TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation. Autophagy 2019;15:1506-22.
45. Kuang Y, Yu Y, Wang C, Li H, Zhou Y, Pan L, et al. FOXS1, frequently inactivated by promoter methylation, inhibited colorectal cancer cell growth by promoting TGFBI degradation through autophagy-lysosome pathway. J Adv Res 2025;77:623-36.
- Abstract Viewed: 169 times
- PDF Downloaded: 97 times