Chronic hypoxia stabilizes 3βHSD1 via autophagy suppression
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment is androgen deprivation therapy. Unfortunately, despite initial treatment response, resistance nearly always develops, and disease progresses to castration-resistant prostate cancer (CRPC), which remains driven by non-gonadal androgens synthesized in prostate cancer tissues. 3β-Hydroxysteroid dehydrogenase/Δ5-->4 isomerase 1 (3βHSD1) catalyzes the rate-limiting step in androgen synthesis. However, how 3βHSD1, especially the "adrenal-permissive" 3βHSD1(367T) that permits tumor synthesis of androgen from dehydroepiandrosterone (DHEA), is regulated at the protein level is not well understood. Here, we investigate how hypoxia regulates 3βHSD1(367T) protein levels. Our results show that, in vitro, hypoxia stabilizes 3βHSD1 protein by suppressing autophagy. Autophagy inhibition promotes 3βHSD1-dependent tumor progression. Hypoxia represses transcription of autophagy-related (ATG) genes by decreasing histone acetylation. Inhibiting deacetylase (HDAC) restores ATG gene transcription under hypoxia. Therefore, HDAC inhibition may be a therapeutic target for hypoxic tumor cells.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
|---|---|
| Enthalten in: |
Cell reports - 43(2024), 1 vom: 23. Jan., Seite 113575 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Qin, Liang [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 26.01.2024 Date Revised 12.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.celrep.2023.113575 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366724002 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366724002 | ||
| 003 | DE-627 | ||
| 005 | 20240213232733.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240108s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.celrep.2023.113575 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1290.xml |
| 035 | |a (DE-627)NLM366724002 | ||
| 035 | |a (NLM)38181788 | ||
| 035 | |a (PII)S2211-1247(23)01587-5 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Qin, Liang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Chronic hypoxia stabilizes 3βHSD1 via autophagy suppression |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.01.2024 | ||
| 500 | |a Date Revised 12.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment is androgen deprivation therapy. Unfortunately, despite initial treatment response, resistance nearly always develops, and disease progresses to castration-resistant prostate cancer (CRPC), which remains driven by non-gonadal androgens synthesized in prostate cancer tissues. 3β-Hydroxysteroid dehydrogenase/Δ5-->4 isomerase 1 (3βHSD1) catalyzes the rate-limiting step in androgen synthesis. However, how 3βHSD1, especially the "adrenal-permissive" 3βHSD1(367T) that permits tumor synthesis of androgen from dehydroepiandrosterone (DHEA), is regulated at the protein level is not well understood. Here, we investigate how hypoxia regulates 3βHSD1(367T) protein levels. Our results show that, in vitro, hypoxia stabilizes 3βHSD1 protein by suppressing autophagy. Autophagy inhibition promotes 3βHSD1-dependent tumor progression. Hypoxia represses transcription of autophagy-related (ATG) genes by decreasing histone acetylation. Inhibiting deacetylase (HDAC) restores ATG gene transcription under hypoxia. Therefore, HDAC inhibition may be a therapeutic target for hypoxic tumor cells | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a 3βHSD1 | |
| 650 | 4 | |a CP: Cancer | |
| 650 | 4 | |a CP: Molecular biology | |
| 650 | 4 | |a androgen synthesis | |
| 650 | 4 | |a autophagy | |
| 650 | 4 | |a enzyme | |
| 650 | 4 | |a germline | |
| 650 | 4 | |a hypoxia | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a prostate cancer | |
| 650 | 4 | |a protein | |
| 650 | 4 | |a steroid | |
| 650 | 7 | |a Androgens |2 NLM | |
| 650 | 7 | |a Androgen Antagonists |2 NLM | |
| 650 | 7 | |a Receptors, Androgen |2 NLM | |
| 700 | 1 | |a Berk, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Yoon-Mi |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Di |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Ziqi |e verfasserin |4 aut | |
| 700 | 1 | |a Chakraborty, Abhishek A |e verfasserin |4 aut | |
| 700 | 1 | |a Sharifi, Nima |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cell reports |d 2012 |g 43(2024), 1 vom: 23. Jan., Seite 113575 |w (DE-627)NLM217067492 |x 2211-1247 |7 nnns |
| 773 | 1 | 8 | |g volume:43 |g year:2024 |g number:1 |g day:23 |g month:01 |g pages:113575 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.celrep.2023.113575 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 43 |j 2024 |e 1 |b 23 |c 01 |h 113575 | ||