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Cellular and Molecular Biology

SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation in pancreatic cancer

British Journal of Cancer volume 133, pages 1441–1453 (2025) Cite this article

Subjects

Abstract

Background

Activin A/Smad signaling plays an important role in promoting cancer stemness and chemoresistance in pancreatic ductal adenocarcinoma (PDAC), however the precise regulation on the termination of this pathway has not been fully understood.

Methods

LncRNA SLC7A11-AS1 interacting proteins were identified through RNA pull-down followed by LC-MS/MS. The protein interaction was analyzed by co-immunoprecipitation. The expressions of SLC7A11-AS1 and activin A in tissue microarray were analyzed by FISH and immunofluerescence. Tumor xenograft mice models were established for in vivo experiments.

Results

Overexpression of SLC7A11-AS1 enhanced the activin A-induced Smad2/3 phosphorylation and promoted cancer stemness properties in PDAC cells. Mechanically, SLC7A11-AS1 interacts with scaffold protein RSL1D1. This interaction disrupts PPM1A myristoylation by suppressing the recruitment of PPM1A and myristoyltransferase NMT1 to RSL1D1, leading to prolonged activation of activin A/Smad signaling through the delay of Smad2/3 dephosphorylation. Co-overexpression of SLC7A11-AS1 and activin A were found in pancreatic patients, and related with the extremely short survival periods. Knockdown of SLC7A11-AS1 and blockade of activin A signaling significantly reduced gemcitabine resistance in PDAC in vitro and in vivo.

Conclusions

SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation. Targeting both SLC7A11-AS1 and activin A may offer a potential therapeutic strategy for overcoming gemcitabine resistance in PDAC.

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Fig. 1: Co-overexpression of SLC7A11-AS1 and activin A enhances PDAC stemness.
The alternative text for this image may have been generated using AI.
Fig. 2: SLC7A11-AS1 suppresses Smad2/3 dephosphorylation.
The alternative text for this image may have been generated using AI.
Fig. 3: SLC7A11-AS1 prevents Smad2/3 dephosphorylation through inhibition of PPM1A myristoylation.
The alternative text for this image may have been generated using AI.
Fig. 4: SLC7A11-AS1 interacts with RSL1D1.
The alternative text for this image may have been generated using AI.
Fig. 5: SLC7A11-AS1 suppresses the recruitment of PPM1A and NMT1 to RSL1D1.
The alternative text for this image may have been generated using AI.
Fig. 6: Targeting SLC7A11-AS1 and activin A sensitizes PDAC cells to gemcitabine.
The alternative text for this image may have been generated using AI.

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Data availability

Data supporting the figures generated are available from authors under written demand. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository with the dataset identifier PXD064849.

References

  1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49.

    PubMed  Google Scholar 

  2. Yang C, Zhu S, Yang H, Deng S, Fan P, Li M, et al. USP44 suppresses pancreatic cancer progression and overcomes gemcitabine resistance by deubiquitinating FBP1. Am J Cancer Res. 2019;9:1722.

    PubMed  PubMed Central  CAS  Google Scholar 

  3. Chen KH, Guo Y, Li L, Qu S, Zhao W, Lu QT, et al. Cancer stem cell‐like characteristics and telomerase activity of the nasopharyngeal carcinoma radioresistant cell line CNE‐2R. Cancer Med. 2018;7:4755.

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Alcalá S, Sancho P, Martinelli P, Navarro D, Pedrero C, Martín-Hijano L, et al. ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity. Nat Commun. 2020;11:2682.

    PubMed  PubMed Central  Google Scholar 

  5. Zhang Z, Duan Q, Zhao H, Liu T, Wu H, Shen Q, et al. Gemcitabine treatment promotes pancreatic cancer stemness through the Nox/ROS/NF-κB/STAT3 signaling cascade. Cancer Lett. 2016;382:53–63.

    PubMed  CAS  Google Scholar 

  6. Li K, Zhang Z, Mei Y, Yang Q, Qiao S, Ni C, et al. Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition. Theranostics. 2021;11:3196–212.

    PubMed  PubMed Central  CAS  Google Scholar 

  7. Lonardo E, Hermann PC, Mueller MT, Huber S, Balic A, Miranda-Lorenzo I, et al. Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell. 2011;9:433–46.

    PubMed  CAS  Google Scholar 

  8. Chang KP, Kao HK, Liang Y, Cheng MH, Chang YL, Liu SC, et al. Overexpression of activin A in oral squamous cell carcinoma: association with poor prognosis and tumor progression. Ann Surg Oncol. 2010;17:1945–56.

    PubMed  Google Scholar 

  9. Hoda MA, Münzker J, Ghanim B, Schelch K, Klikovits T, Laszlo V, et al. Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells. Br J Cancer. 2012;107:1978–86.

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Bashir M, Damineni S, Mukherjee G, Kondaiah P. Activin-A signaling promotes epithelial-mesenchymal transition, invasion, and metastatic growth of breast cancer. NPJ Breast Cancer. 2015;1:15007.

    PubMed  PubMed Central  CAS  Google Scholar 

  11. Ge J, Sun H, Li J, Shan Y, Zhao Y, Liao F, et al. Involvement of CHOP in activin A-induced myeloma NS-1 cell apoptosis. Oncol Rep. 2019;42:2644–54.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Hong Y, Gong L, Yu B, Dong Y. PPM1A suppresses the proliferation and invasiveness of RCC cells via Smad2/3 signaling inhibition. J Recept Sig Transduct Res. 2021;41:245–54.

    CAS  Google Scholar 

  13. Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, et al. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell. 2006;125:915–28.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Zhu F, Xie N, Jiang Z, Li G, Ma L, Tong T. The cellular senescence-inhibited gene is essential for PPM1A myristoylation to modulate transforming growth factor β signaling. Mol Cell Biol. 2018;38:e00414-18.

    PubMed  PubMed Central  Google Scholar 

  15. Chida T, Ando M, Matsuki T, Masu Y, Nagaura Y, Takano-Yamamoto T, et al. N-Myristoylation is essential for protein phosphatases PPM1A and PPM1B to dephosphorylate their physiological substrates in cells. Biochem J. 2013;449:741–9.

    PubMed  CAS  Google Scholar 

  16. Liu Y, Fan X, Zhao Z, Shan X. LncRNA SLC7A11-AS1 contributes to lung cancer progression through facilitating TRAIP expression by inhibiting miR-4775. OncoTargets Ther. 2020;13:6295–302.

    CAS  Google Scholar 

  17. Yu L, Li J, Xiao M. LncRNA SLC7A11-AS1 stabilizes CTCF by inhibiting its UBE3A-mediated ubiquitination to promote melanoma metastasis. Am J Cancer Res. 2023;13:6256–69.

    PubMed  PubMed Central  CAS  Google Scholar 

  18. Zeng FL, Lin J, Xie X, Xie YK, Zhang JH, Xu D, et al. LncRNA SLC7A11-AS1 promotes the progression of hepatocellular carcinoma by mediating KLF9 ubiquitination. Neoplasma. 2023;70:361–74.

    PubMed  CAS  Google Scholar 

  19. Yang Q, Li K, Huang X, Zhao C, Mei Y, Li X, et al. lncRNA SLC7A11-AS1 promotes chemoresistance by blocking SCFβ-TRCP-mediated degradation of NRF2 in pancreatic cancer. Mol Ther Nucleic Acids. 2020;19:974–85.

    PubMed  PubMed Central  CAS  Google Scholar 

  20. Gao Y, Zhang Z, Li K, Gong L, Yang Q, Huang X, et al. Linc-DYNC2H1-4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells. Cell Death Dis. 2017;8:e2924.

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Yang C, Liu X, Cheng T, Xiao R, Gao Q, Ming F, et al. LYAR suppresses beta interferon induction by targeting phosphorylated interferon regulatory factor 3. J Virol. 2019;93:e00769-19.

    PubMed  PubMed Central  Google Scholar 

  22. Mancinelli G, Torres C, Krett N, Bauer J, Castellanos K, McKinney R, et al. Role of stromal activin A in human pancreatic cancer and metastasis in mice. Sci Rep. 2021;11:7986.

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Zhong X, Pons M, Poirier C, Jiang Y, Liu J, Sandusky GE, et al. The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy. J Cachexia Sarcopenia Muscle. 2019;10:1083–101.

    PubMed  PubMed Central  Google Scholar 

  24. Togashi Y, Kogita A, Sakamoto H, Hayashi H, Terashima M, de Velasco MA, et al. Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer. Cancer Lett. 2015;356:819–27.

    PubMed  CAS  Google Scholar 

  25. Yang J, Jiang W. The role of SMAD2/3 in human embryonic stem cells. Front Cell Dev Biol. 2020;8:653.

    PubMed  PubMed Central  Google Scholar 

  26. DaCosta Byfield S, Major C, Laping NJ, Roberts AB. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2004;65:744–52.

    PubMed  Google Scholar 

  27. Skrinjar P, Schwarz M, Lexmüller S, Mechtler TP, Zeyda M, Greber-Platzer S, et al. Rapid and modular assembly of click substrates to assay enzyme activity in the newborn screening of lysosomal storage disorders. ACS Cent Sci. 2018;4:1688–96.

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Kim S, Yang X, Li Q, Wu M, Costyn L, Beharry Z, et al. Myristoylation of SRC kinase mediates SRC-induced and high-fat diet-accelerated prostate tumor progression in mice. J Biol Chem. 2017;292:18422–33.

    PubMed  PubMed Central  CAS  Google Scholar 

  29. Kim S, Alsaidan OA, Goodwin O, Li Q, Sulejmani E, Han Z, et al. Blocking myristoylation of SRC inhibits its kinase activity and suppresses prostate cancer progression. Cancer Res. 2017;77:6950–62.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Ma L, Chang N, Guo S, Li Q, Zhang Z, Wang W, et al. CSIG inhibits PTEN translation in replicative senescence. Mol Cell Biol. 2008;28:6290–301.

    PubMed  PubMed Central  CAS  Google Scholar 

  31. Oshima Y, Ouchi N, Shimano M, Pimentel DR, Papanicolaou KN, Panse KD, et al. Activin A and Follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation. 2009;120:1606–15.

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Huang X, Pan L, Zuo Z, Li M, Zeng L, Li R, et al. LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling. Nat Commun. 2021;12:3830.

    PubMed  PubMed Central  CAS  Google Scholar 

  33. Jiang Y, Guo H, Tong T, Xie F, Qin X, Wang X, et al. lncRNA lnc-POP1-1 upregulated by VN1R5 promotes cisplatin resistance in head and neck squamous cell carcinoma through interaction with MCM5. Mol Ther J Am Soc Gene Ther. 2022;30:448–67.

    CAS  Google Scholar 

  34. Sun Y, Cai M, Zhong J, Yang L, Xiao J, Jin F, et al. The long noncoding RNA lnc-ob1 facilitates bone formation by upregulating Osterix in osteoblasts. Nat Metab. 2019;1:485–96.

    PubMed  CAS  Google Scholar 

  35. Xiu B, Chi Y, Liu L, Chi W, Zhang Q, Chen J, et al. LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription. Mol Cancer. 2019;18:187.

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Abdel Mouti M, Pauklin S. TGFB1/INHBA Homodimer/Nodal-SMAD2/3 signaling network: a pivotal molecular target in PDAC treatment. Mol Ther J Am Soc Gene Ther. 2021;29:920–36.

    CAS  Google Scholar 

  37. Zhuang J, Shen L, Yang L, Huang X, Lu Q, Cui Y, et al. TGFβ1 promotes gemcitabine resistance through regulating the LncRNA-LET/NF90/miR-145 signaling axis in bladder cancer. Theranostics. 2017;7:3053–67.

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Feng D, Zhou J, Liu H, Wu X, Li F, Zhao J, et al. Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage. Sci Adv. 2022;8:eabq2423.

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Coates RF, Gardner JA, Gao Y, Cortright VM, Mitchell JM, Ashikaga T, et al. Significance of positive and inhibitory regulators in the TGF-β signaling pathway in colorectal cancers. Hum Pathol. 2017;66:34–9.

    PubMed  CAS  Google Scholar 

  40. Xu PC, You M, Yu SY, Luan Y, Eldani M, Caffrey TC, et al. Visceral adipose tissue remodeling in pancreatic ductal adenocarcinoma cachexia: the role of activin A signaling. Sci Rep. 2022;12:1659.

    PubMed  PubMed Central  Google Scholar 

  41. Sidis Y, Mukherjee A, Keutmann H, Delbaere A, Sadatsuki M, Schneyer A. Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins. Endocrinology. 2006;147:3586–97.

    PubMed  CAS  Google Scholar 

  42. Sharma TP, Nett TM, Karsch FJ, Phillips DJ, Lee JS, Herkimer C, et al. Neuroendocrine control of FSH secretion: IV. hypothalamic control of pituitary FSH-regulatory proteins and their relationship to changes in FSH synthesis and secretion. Biol Reprod. 2012;86:171.

    PubMed  PubMed Central  Google Scholar 

  43. Benizri S, Gissot A, Martin A, Vialet B, Grinstaff MW, Barthélémy P. Bioconjugated oligonucleotides: recent developments and therapeutic applications. Bioconjug Chem. 2019;30:366–83.

    PubMed  PubMed Central  CAS  Google Scholar 

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Funding

This work was supported by National Natural Science Foundation of China (82172582, 52372267), He’nan Key Science and Technology Research (242102311235) and Heilongjiang Province Outstanding Young Teachers Basic Research Support Program (YQJH2023048).

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Authors and Affiliations

  1. School of Life Science and Technology, Harbin Institute of Technology, Harbin, China

    Mengmeng Li, Fei Wang, Xuemei Huang, Huan Nie & Huanjie Yang

  2. Harbin Medical University, Harbin, China

    Zhicheng Zhang

  3. College of Life Science and Agriculture Forestry, Qiqihar University, Qiqihar, China

    Qingzhu Yang

  4. School of Medicine and Health, Harbin Institute of Technology, Harbin, China

    Kai Li

  5. Zhengzhou Research Institute of Harbin Institute of Technology, Zhengzhou, China

    Kai Li

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Contributions

ML: Writing–original draft, methodology, investigation, validation, formal analysis, data curation. ZZ: Investigation, formal analysis. QY: Investigation, validation. FW: Investigation, validation. XH: Investigation. HN: Supervision. KL: Methodology, supervision, funding acquisition. HY: Project administration, conceptualization, resources, writing–review and editing, funding acquisition.

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Correspondence to Kai Li or Huanjie Yang.

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All the animal procedures were approved by the Ethics Committee of the School of Life Science and Technology, Harbin Institute of Technology, and conducted in accordance with NIH guidelines for the Care and Use of Laboratory Animals.

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Li, M., Zhang, Z., Yang, Q. et al. SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation in pancreatic cancer. Br J Cancer 133, 1441–1453 (2025). https://doi.org/10.1038/s41416-025-03149-4

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