Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone

Liu

et al. 2020

Aging

Self Cite

Steroidogenic enzymes are crucial in prostate cancer (PCa) progression. 17β-Hydroxysteroid dehydrogenase type 4 (HSD17B4), encoded by HSD17B4, lacks catalytic capacity in androgen metabolism. Now the detailed role and molecular mechanism of PCa development are largely unknown. Here we showed that the expression of HSD17B4 was increased in PCa tissues compared to paired paratumor tissues. HSD17B4 knockdown in PCa cells significantly suppressed its proliferation, migration and invasion, while overexpressing HSD17B4 had opposite effects. Mechanistically, we found that the protein level of HSD17B4 was regulated by its acetylation at lysine 669(K669). Dihydroxytestosterone (DHT) treatment increased HSD17B4 acetylation and then promoted its degradation via chaperone-mediated autophagy (CMA). SIRT3 directly interacted with HSD17B4 to inhibit its acetylation and enhance its stability. In addition, we identified CREBBP as a regulator of the K669 acetylation and degradation of HSD17B4, affecting PC cell proliferation, migration and invasion. Notably, in PCa tissues and paired paratumor tissues, the level of HSD17B4 was negatively correlated with its K669 acetylation. Taken together, this study identified a novel role of HSD17B4 in PCa progression and suggested that HSD17B4 and its upstream regulators may be potential therapeutic targets for PCa intervention.

Section: Resultsmentioning

confidence: 99%

“…Previous studies have suggested that SIRT3 is responsible for acetylation of HSD17B4 in breast cancer cells [ 22 ]. We transfected HA-tagged SIRT3 and FLAG-tagged HSD17B4 into LNCaP cells and determined the acetylation level of HSD17B4 by western blotting.…”

Section: Resultsmentioning

confidence: 99%

Acetylation-mediated degradation of HSD17B4 regulates the progression of prostate cancer

Liu

et al. 2020

Aging

Self Cite

“…The association between dysregulation of hormone metabolism and human breast cancer and sirtuin expression was described by Zhang et al [ 47 ]. 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) catalyzes the conversion of estradiol (E2) to estrone (E1), and is associated with the pathogenesis and development of various cancers, especially those which are hormone-dependent.…”

Section: Sirtuins In Typical Women’s Cancersmentioning

confidence: 99%

Sirtuins—The New Important Players in Women’s Gynecological Health

et al. 2021

The participation of sirtuins in the regulation of oxidative stress and inflammation lies at the basis of their possible modes of action and is related to their expression in various cell structures; their location in the mitochondria and blood plasma has been indicated as of primary importance. Despite many existing studies, research on sirtuins continues to present an opportunity to discover new functions and dependencies, especially when it comes to women’s gynecological health. Sirtuins have a significant role in both the formation and the course of many gynecological diseases. Their role is particularly important and well documented in the course of the development of cancer within the female reproductive organs; however, disturbances observed in the ovary and oocyte as well as in follicular fluid are also widely investigated. Additionally, sirtuins take part in some gynecological disturbances as regulative factors in pathways associated with insulin resistance, glucose and lipids metabolism disorders. In this review, we would like to summarize the existing knowledge about sirtuins in the manner outlined above.

“…There is a correlation between CMA activity and metastasis in breast cancer [ 75 ]. CMA degrades the multifunctional protein HSD17B4, which modulates the properties for the invasion and migration of cells [ 103 ]. Moreover, decreased CMA by the modulation of LAMP2A inhibits tumor growth and metastasis by upregulating ATG5-dependent macrophages in human breast cancer [ 75 ].…”

Section: The Bipolar Role Of Autophagy In Cancermentioning

confidence: 99%

The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy

Yun¹,

Jeon²,

et al. 2020

IJMS

Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal components. Afterward, autophagosomes assemble with lysosomes to recycle or remove degradative cargo. The regulation of autophagy has bipolar roles in cancer suppression and promotion in diverse cancers. Furthermore, autophagy modulates the features of tumorigenesis, cancer metastasis, cancer stem cells, and drug resistance against anticancer agents. Some autophagy regulators are used to modulate autophagy for anticancer therapy but the dual roles of autophagy limit their application in anticancer therapy, and present as the main reason for therapy failure. In this review, we summarize the mechanisms of autophagy, tumorigenesis, metastasis, cancer stem cells, and resistance against anticancer agents. Finally, we discuss whether targeting autophagy is a promising and effective therapeutic strategy in anticancer therapy.