PIAS Family in Cancer: from Basic Mechanisms to Clinical Applications

Overview

Journal Front Oncol

Specialty Oncology

Date 2024 Apr 9

PMID 38590645

Authors

Xiaomeng Li

Azhar Rasul

Farzana Sharif

Mudassir Hassan

Affiliations

Soon will be listed here.

Abstract

Protein inhibitors of activated STATs (PIAS) are proteins for cytokine signaling that activate activator-mediated gene transcription. These proteins, as versatile cellular regulators, have been described as regulators of approximately 60 proteins. Dysregulation of PIAS is associated with inappropriate gene expression that promotes oncogenic signaling in multiple cancers. Multiple lines of evidence have revealed that PIAS family members show modulated expressions in cancer cells. Most frequently reported PIAS family members in cancer development are PIAS1 and PIAS3. SUMOylation as post-translational modifier regulates several cellular machineries. PIAS proteins as SUMO E3 ligase factor promotes SUMOylation of transcription factors tangled cancer cells for survival, proliferation, and differentiation. Attenuated PIAS-mediated SUMOylation mechanism is involved in tumorigenesis. This review article provides the PIAS/SUMO role in the modulation of transcriptional factor control, provides brief update on their antagonistic function in different cancer types with particular focus on PIAS proteins as a bonafide therapeutic target to inhibit STAT pathway in cancers, and summarizes natural activators that may have the ability to cure cancer.

Citing Articles

Expression levels of protein inhibitor of activated STAT (PIAS) family genes in Parkinson's disease patients: results from a case-control study.

Gavabari F, Rastegari-Pouyani M, Afshar S, Mazdeh M, Bahramian A, Shahidi S Acta Neurol Belg. 2025; .

PMID: 40016540 DOI: 10.1007/s13760-025-02752-9.

Blockade of the STAT3/BCL-xL Axis Leads to the Cytotoxic and Cisplatin-Sensitizing Effects of Fucoxanthin, a Marine-Derived Carotenoid, on Human Bladder Urothelial Carcinoma Cells.

Dai W, Chen T, Peng T, He Y, Hsu C, Chang C Mar Drugs. 2025; 23(2).

PMID: 39997178 PMC: 11857094. DOI: 10.3390/md23020054.

PIAS family gene expression: implications for prognosis, immunomodulation, and chemotherapy response.

Shu H, Chen X, Zhao J, Li P, Sun Z Am J Transl Res. 2024; 16(11):6346-6364.

PMID: 39678595 PMC: 11645565. DOI: 10.62347/JRDP4018.

References

Sun Q, Qing W, Qi R, Zou M, Gong L, Liu Y . Inhibition of Sumoylation Alleviates Oxidative Stress-induced Retinal Pigment Epithelial Cell Senescence and Represses Proinflammatory Gene Expression. Curr Mol Med. 2019; 18(9):575-583. DOI: 10.2174/1566524019666190107154250. View

Long J, Wang G, Matsuura I, He D, Liu F . Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3). Proc Natl Acad Sci U S A. 2003; 101(1):99-104. PMC: 314145. DOI: 10.1073/pnas.0307598100. View

Gur I, Fujiwara K, Hasegawa K, Yoshikawa K . Necdin promotes ubiquitin-dependent degradation of PIAS1 SUMO E3 ligase. PLoS One. 2014; 9(6):e99503. PMC: 4049815. DOI: 10.1371/journal.pone.0099503. View

Dai X, Ahn K, Kim C, Siveen K, Ong T, Shanmugam M . Ascochlorin, an isoprenoid antibiotic inhibits growth and invasion of hepatocellular carcinoma by targeting STAT3 signaling cascade through the induction of PIAS3. Mol Oncol. 2015; 9(4):818-33. PMC: 5528777. DOI: 10.1016/j.molonc.2014.12.008. View

Sundvall M, Korhonen A, Vaparanta K, Anckar J, Halkilahti K, Salah Z . Protein inhibitor of activated STAT3 (PIAS3) protein promotes SUMOylation and nuclear sequestration of the intracellular domain of ErbB4 protein. J Biol Chem. 2012; 287(27):23216-26. PMC: 3391121. DOI: 10.1074/jbc.M111.335927. View

Hou G, Zhao X, Li L, Yang Q, Liu X, Huang C . SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs. Nucleic Acids Res. 2021; 49(5):2859-2877. PMC: 7969013. DOI: 10.1093/nar/gkab065. View

Bettermann K, Benesch M, Weis S, Haybaeck J . SUMOylation in carcinogenesis. Cancer Lett. 2011; 316(2):113-25. DOI: 10.1016/j.canlet.2011.10.036. View

Li H, Gao H, Bijukchhe S, Wang Y, Li T . PIAS3 may represent a potential biomarker for diagnosis and therapeutic of human colorectal cancer. Med Hypotheses. 2013; 81(6):1151-4. DOI: 10.1016/j.mehy.2013.09.022. View

Pedras M, Montaut S, Suchy M . Phytoalexins from the crucifer rutabaga: structures, syntheses, biosyntheses, and antifungal activity. J Org Chem. 2004; 69(13):4471-6. DOI: 10.1021/jo049648a. View

10.

Brown J, Conn K, Wasson P, Charman M, Tong L, Grant K . SUMO Ligase Protein Inhibitor of Activated STAT1 (PIAS1) Is a Constituent Promyelocytic Leukemia Nuclear Body Protein That Contributes to the Intrinsic Antiviral Immune Response to Herpes Simplex Virus 1. J Virol. 2016; 90(13):5939-5952. PMC: 4907222. DOI: 10.1128/JVI.00426-16. View

11.

Su D, Li X, Chen J, Dou J, Fang G, Luo C . MiR-543 inhibits proliferation and metastasis of human colorectal cancer cells by targeting PLAS3. Eur Rev Med Pharmacol Sci. 2020; 24(17):8812-8821. DOI: 10.26355/eurrev_202009_22820. View

12.

Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M . The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017; 15(1):23. PMC: 5480189. DOI: 10.1186/s12964-017-0177-y. View

13.

Wu R, Fang J, Liu M, A J, Liu J, Chen W . SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation. J Biol Chem. 2020; 295(19):6741-6753. PMC: 7212658. DOI: 10.1074/jbc.RA119.012338. View

14.

Rabellino A, Andreani C, Scaglioni P . The Role of PIAS SUMO E3-Ligases in Cancer. Cancer Res. 2017; 77(7):1542-1547. PMC: 5380518. DOI: 10.1158/0008-5472.CAN-16-2958. View

15.

Yin H, Yu Y . Identification of the targets of hematoporphyrin derivative in lung adenocarcinoma using integrated network analysis. Biol Res. 2019; 52(1):4. PMC: 6360726. DOI: 10.1186/s40659-019-0213-z. View

16.

Nakagawa K, Kohara T, Uehata Y, Miyakawa Y, Sato-Ueshima M, Okubo N . PIAS3 enhances the transcriptional activity of HIF-1α by increasing its protein stability. Biochem Biophys Res Commun. 2015; 469(3):470-6. DOI: 10.1016/j.bbrc.2015.12.047. View

17.

Wei J, Costa C, Ding Y, Zou Z, Yu L, Sanchez J . mRNA expression of BRCA1, PIAS1, and PIAS4 and survival after second-line docetaxel in advanced gastric cancer. J Natl Cancer Inst. 2011; 103(20):1552-6. DOI: 10.1093/jnci/djr326. View

18.

Jiang M, Zhang W, Zhang R, Liu P, Ye Y, Yu W . Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer. Oncogene. 2020; 39(24):4681-4694. DOI: 10.1038/s41388-020-1322-4. View

19.

Nayak A, Muller S . SUMO-specific proteases/isopeptidases: SENPs and beyond. Genome Biol. 2014; 15(7):422. PMC: 4281951. DOI: 10.1186/s13059-014-0422-2. View

20.

Lara-Urena N, Jafari V, Garcia-Dominguez M . Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases. Int J Mol Sci. 2022; 23(14). PMC: 9316396. DOI: 10.3390/ijms23148012. View