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postgraduate thesis: Protein arginine methylation of BAG5 by PRMT6 regulates autophagy in hepatocellular carcinoma tumours
Title | Protein arginine methylation of BAG5 by PRMT6 regulates autophagy in hepatocellular carcinoma tumours |
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Authors | |
Advisors | |
Issue Date | 2019 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Che, N.. (2019). Protein arginine methylation of BAG5 by PRMT6 regulates autophagy in hepatocellular carcinoma tumours. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Autophagy is a major catabolism to maintain cellular homeostasis in response to
environmental changes by removing harmful intracellular aggregates and damaged
organelles. Meanwhile, this catabolic process provides a route for cancer cells to
adapt and survive from a complicated and stressful tumour microenvironment. As
a result, extensive studies were conducted to focus on the potential of autophagy
inhibition to enhance efficacy of conventional treatment regimen in treating cancers.
However, current clinical trials failed to deliver any promising anticancer outcomes
of targeting autophagy, including hepatocellular carcinoma (HCC). In order to
exploit this vulnerability as anticancer therapy, our full understanding of the precise
mechanism is necessary. Our recent study found out a key post-translational
modification enzyme, protein arginine methyltransferase 6 (PRMT6), was
frequently downregulated in HCC and this downregulation exerted its gain-offunctions
in HCC tumourigenesis (Chan et al. Cell Rep 2018). Our current study
characterised an inhibitory role of PRMT6 in autophagy via protein arginine
methylation in HCC. Mechanistically, we found out Bcl-2 associated athanogene 5
(BAG5) was an interacting partner of PRMT6 by mass spectrometry. We further
demonstrated that PRMT6 methylated BAG5 on the 15th and 24th arginine residues
of its N-terminus to recruit and to degrade its interacting partner, heat shock cognate
70 (HSPA8/HSC70), a well-known autophagy player. Besides, we demonstrated
that BAG5 was important in promoting HCC properties and itself was required to
govern the stability of HSC70 for autophagy induction. By in vitro and in vivo
experiments, we also demonstrated that BAG5 was a downstream effector of
PRMT6 in regulating autophagy. Our results displayed that HCC cells with PRMT6
downregulation were dependent on autophagy for cell survival and targeting
autophagy sensitised them to sorafenib treatment. Taken together, our findings in
this study suggest PRMT6 downregulation in HCC favoured autophagy induction
and provide support for HCC tumourigenesis through modulating BAG5
functionalities. Most importantly, PRMT6 can be used as a prognostic marker for
autophagy inhibition as a combination therapy with sorafenib, suggesting targeting
this mechanism may provide novel therapeutic insights for this deadly disease.
|
Degree | Doctor of Philosophy |
Subject | Liver - Cancer - Pathogenesis Arginine - Methylation |
Dept/Program | Biomedical Sciences |
Persistent Identifier | http://hdl.handle.net/10722/279737 |
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Ma, SKY | - |
dc.contributor.advisor | Guan, X | - |
dc.contributor.author | Che, Noélia | - |
dc.date.accessioned | 2019-12-10T10:04:42Z | - |
dc.date.available | 2019-12-10T10:04:42Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Che, N.. (2019). Protein arginine methylation of BAG5 by PRMT6 regulates autophagy in hepatocellular carcinoma tumours. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/279737 | - |
dc.description.abstract | Autophagy is a major catabolism to maintain cellular homeostasis in response to environmental changes by removing harmful intracellular aggregates and damaged organelles. Meanwhile, this catabolic process provides a route for cancer cells to adapt and survive from a complicated and stressful tumour microenvironment. As a result, extensive studies were conducted to focus on the potential of autophagy inhibition to enhance efficacy of conventional treatment regimen in treating cancers. However, current clinical trials failed to deliver any promising anticancer outcomes of targeting autophagy, including hepatocellular carcinoma (HCC). In order to exploit this vulnerability as anticancer therapy, our full understanding of the precise mechanism is necessary. Our recent study found out a key post-translational modification enzyme, protein arginine methyltransferase 6 (PRMT6), was frequently downregulated in HCC and this downregulation exerted its gain-offunctions in HCC tumourigenesis (Chan et al. Cell Rep 2018). Our current study characterised an inhibitory role of PRMT6 in autophagy via protein arginine methylation in HCC. Mechanistically, we found out Bcl-2 associated athanogene 5 (BAG5) was an interacting partner of PRMT6 by mass spectrometry. We further demonstrated that PRMT6 methylated BAG5 on the 15th and 24th arginine residues of its N-terminus to recruit and to degrade its interacting partner, heat shock cognate 70 (HSPA8/HSC70), a well-known autophagy player. Besides, we demonstrated that BAG5 was important in promoting HCC properties and itself was required to govern the stability of HSC70 for autophagy induction. By in vitro and in vivo experiments, we also demonstrated that BAG5 was a downstream effector of PRMT6 in regulating autophagy. Our results displayed that HCC cells with PRMT6 downregulation were dependent on autophagy for cell survival and targeting autophagy sensitised them to sorafenib treatment. Taken together, our findings in this study suggest PRMT6 downregulation in HCC favoured autophagy induction and provide support for HCC tumourigenesis through modulating BAG5 functionalities. Most importantly, PRMT6 can be used as a prognostic marker for autophagy inhibition as a combination therapy with sorafenib, suggesting targeting this mechanism may provide novel therapeutic insights for this deadly disease. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Liver - Cancer - Pathogenesis | - |
dc.subject.lcsh | Arginine - Methylation | - |
dc.title | Protein arginine methylation of BAG5 by PRMT6 regulates autophagy in hepatocellular carcinoma tumours | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biomedical Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_991044168864103414 | - |
dc.date.hkucongregation | 2019 | - |
dc.identifier.mmsid | 991044168864103414 | - |