TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells
ATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to t...
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MDPI AG
2022-01-01
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| author | Raffaella Petruzzelli Marta Mariniello Rossella De Cegli Federico Catalano Floriana Guida Elia Di Schiavi Roman S. Polishchuk |
| author_facet | Raffaella Petruzzelli Marta Mariniello Rossella De Cegli Federico Catalano Floriana Guida Elia Di Schiavi Roman S. Polishchuk |
| author_sort | Raffaella Petruzzelli |
| collection | DOAJ |
| description | ATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to the bile at the apical surface of hepatocytes. In addition to liver, high ATP7B expression has been reported in tumors with elevated resistance to platinum (Pt)-based chemotherapy. Chemoresistance to Pt drugs represents the current major obstacle for the treatment of large cohorts of cancer patients. Although the mechanisms underlying Pt-tolerance are still ambiguous, accumulating evidence suggests that lysosomal sequestration of Pt drugs by ion transporters (including ATP7B) might significantly contribute to drug resistance development. In this context, signaling mechanisms regulating the expression of transporters such as ATP7B are of great importance. Considering this notion, we investigated whether ATP7B expression in Pt-resistant cells might be driven by transcription factor EB (TFEB), a master regulator of lysosomal gene transcription. Using resistant ovarian cancer IGROV-CP20 cells, we found that TFEB directly binds to the predicted coordinated lysosomal expression and regulation (CLEAR) sites in the proximal promoter and first intron region of ATP7B upon Pt exposure. This binding accelerates transcription of luciferase reporters containing ATP7B CLEAR regions, while suppression of TFEB inhibits ATP7B expression and stimulates cisplatin toxicity in resistant cells. Thus, these data have uncovered a Pt-dependent transcriptional mechanism that contributes to cancer chemoresistance and might be further explored for therapeutic purposes. |
| first_indexed | 2024-03-10T01:44:29Z |
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| last_indexed | 2024-03-10T01:44:29Z |
| publishDate | 2022-01-01 |
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| spelling | doaj.art-abe6dc9a58f648cdb1a73d9e10981a922023-11-23T13:17:54ZengMDPI AGCells2073-44092022-01-0111221910.3390/cells11020219TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer CellsRaffaella Petruzzelli0Marta Mariniello1Rossella De Cegli2Federico Catalano3Floriana Guida4Elia Di Schiavi5Roman S. Polishchuk6Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyInstitute of Physiology, Zürich University, Winterthurerstr. 190, CH-8057 Zürich, SwitzerlandTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, 16132 Genoa, ItalyInstitute of Biosciences and BioResources (IBBR), CNR, 80131 Naples, ItalyTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to the bile at the apical surface of hepatocytes. In addition to liver, high ATP7B expression has been reported in tumors with elevated resistance to platinum (Pt)-based chemotherapy. Chemoresistance to Pt drugs represents the current major obstacle for the treatment of large cohorts of cancer patients. Although the mechanisms underlying Pt-tolerance are still ambiguous, accumulating evidence suggests that lysosomal sequestration of Pt drugs by ion transporters (including ATP7B) might significantly contribute to drug resistance development. In this context, signaling mechanisms regulating the expression of transporters such as ATP7B are of great importance. Considering this notion, we investigated whether ATP7B expression in Pt-resistant cells might be driven by transcription factor EB (TFEB), a master regulator of lysosomal gene transcription. Using resistant ovarian cancer IGROV-CP20 cells, we found that TFEB directly binds to the predicted coordinated lysosomal expression and regulation (CLEAR) sites in the proximal promoter and first intron region of ATP7B upon Pt exposure. This binding accelerates transcription of luciferase reporters containing ATP7B CLEAR regions, while suppression of TFEB inhibits ATP7B expression and stimulates cisplatin toxicity in resistant cells. Thus, these data have uncovered a Pt-dependent transcriptional mechanism that contributes to cancer chemoresistance and might be further explored for therapeutic purposes.https://www.mdpi.com/2073-4409/11/2/219ATP7BTFEBGolgiovarian cancerchemoresistance |
| spellingShingle | Raffaella Petruzzelli Marta Mariniello Rossella De Cegli Federico Catalano Floriana Guida Elia Di Schiavi Roman S. Polishchuk TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells Cells ATP7B TFEB Golgi ovarian cancer chemoresistance |
| title | TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells |
| title_full | TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells |
| title_fullStr | TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells |
| title_full_unstemmed | TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells |
| title_short | TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells |
| title_sort | tfeb regulates atp7b expression to promote platinum chemoresistance in human ovarian cancer cells |
| topic | ATP7B TFEB Golgi ovarian cancer chemoresistance |
| url | https://www.mdpi.com/2073-4409/11/2/219 |
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