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. 2022 Mar 7;14(3):e14764.
doi: 10.15252/emmm.202114764. Epub 2022 Jan 11.

THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer

Arnaud Blomme  1 , Coralie Peter  1 , Ernest Mui  2 , Giovanny Rodriguez Blanco  1 , Ning An  3 , Louise M Mason  4 , Lauren E Jamieson  5 , Grace H McGregor  1   2 , Sergio Lilla  1 , Chara Ntala  1   2 , Rachana Patel  1 , Marc Thiry  6 , Sonia H Y Kung  7   8 , Marine Leclercq  3 , Catriona A Ford  1 , Linda K Rushworth  1   2 , David J McGarry  1 , Susan Mason  1 , Peter Repiscak  1 , Colin Nixon  1 , Mark J Salji  2 , Elke Markert  2 , Gillian M MacKay  1 , Jurre J Kamphorst  1   2 , Duncan Graham  5 , Karen Faulds  5 , Ladan Fazli  7   8 , Martin E Gleave  7   8 , Edward Avezov  9 , Joanne Edwards  2 , Huabing Yin  4 , David Sumpton  1 , Karen Blyth  1   2 , Pierre Close  3 , Daniel J Murphy  1   2 , Sara Zanivan  1   2 , Hing Y Leung  1   2
Affiliations

THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer

Arnaud Blomme et al. EMBO Mol Med. .

Abstract

Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.

Keywords: ATF4; ER stress; lipid metabolism; prostate cancer; therapy resistance.

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Figures

Figure 1
Figure 1. Loss of THEM6 impairs PCa tumour growth following ADT

  1. Volcano plot of the differentially modulated proteins in 22rv1 (CRPC) versus CWR22res (HN) tumours. Red and blue dots represent the proteins that are significantly up‐ and down‐regulated, respectively (P‐value < 0.05, FC = 1.5).

  2. Western blot analysis of THEM6 expression in CRPC (22rv1 and LNCaP AI) and HN (CWR22res and LNCaP) prostate orthografts. VCL was used as a sample loading control.

  3. IHC staining of THEM6 expression in CWR22res and 22rv1 orthografts. Scale bar represents 100 µm.

  4. Western blot analysis of THEM6 expression in CTL and THEM6 KO CRPC cells. HSC70 was used as a sample loading control.

  5. Proliferation of CTL and THEM6 KO CRPC cells after 72 h. Data are expressed as a percentage of CTL cells.

  6. Cell stiffness (Young's modulus) of CTL and THEM6 KO CRPC cells measured by atomic force microscopy.

  7. Tumour volume (measured by ultrasound) of CTL and THEM6 KO 22rv1‐derived orthografts developed in surgically castrated mice.

  8. Tumour volume of CTL and THEM6 KO LNCaP AI‐derived xenografts developed in surgically castrated mice.

  9. Tumour volume (measured by ultrasound) of CTL and THEM6 KO CWR22res‐derived orthografts. Orchidectomy was performed 3 weeks after cell implantation.

Data information: Panels (E, G, H, I) Data are presented as mean values ± SD. Panel (F) Centre line corresponds to median of data, top and bottom lines correspond to maximal and minimal values. Statistical analysis: (E, F) One‐way ANOVA with a Dunnett's multiple comparisons test. (G, H) two‐tailed Mann–Whitney U‐test. (I) Kruskal–Wallis test. Data reproducibility: Panel (A) n = 3 tumours per group. Panel (B) n = 1 gel loaded with three prostate orthografts per condition. Panels (C, D) representative image from 3 independent biological experiments. Panel (E) n = 3 independent biological experiments. Panel (F) (up): n = 46 (CTL); 47 (KO1); 49 (KO2) cells measured. Panel (F) (down): n = 31 (CTL); 43 (KO1); 50 (KO2) cells measured. Panels (G, I) n = 5 mice per group. Panel (H) n = 7 mice per group. Source data are available online for this figure.
Figure EV1
Figure EV1. THEM6 is overexpressed following ADT resistance

  1. Volcano plot of the differentially modulated proteins in LNCaP AI (CRPC) versus LNCaP (HN) tumours. Red and blue dots represent the proteins that are significantly up‐ and down‐regulated, respectively (P‐value ≤ 0.05, FC = 1.5).

  2. Western blot analysis of THEM6 expression in PCa cells. HSC70 was used as a sample loading control. Within a panel of PCa cell lines, androgen receptor (AR)‐positive CRPC (namely 22rv1 and LNCaP AI) cells express THEM6 at higher levels than their respective isogenic HN (LNCaP and CWR22res) counterparts.

  3. Representative pictures of haematoxylin/eosin staining on orthografts from CWRres CTL and THEM6 KO tumours. C = cancer cells; N = necrotic area. Scale bar represents 1,000 µm.

Data information: Data reproducibility: (A) n = 3 tumours per group. (B) representative image from three independent biological experiments. (C) representative image from three tumours per group. Source data are available online for this figure.
Figure 2
Figure 2. Loss of THEM6 alters lipid homeostasis
  1. A

    Heatmap illustrating the steady‐state levels of significantly regulated lipids in THEM6 KO 22rv1 cells when compared to CTL (P ≤ 0.05, FC = 1.3). Values are expressed as log2(FC).

  2. B, C

    Changes in lipid content (total amount) observed in THEM6 KO CRPC cells when compared to CTL.

  3. D

    Heatmap illustrating the steady‐state levels of significantly regulated lipids in THEM6 OE CWR22res cells when compared to EV (P ≤ 0.05, FC = 1.2). Values are expressed as log2(FC).

  4. E

    Changes in lipid content (total amount) observed in THEM6 OE CWR22res cells when compared to EV.

  5. F

    Average Raman spectra of CWR22res CTL and THEM6 KO orthografts.

  6. G, H

    Quantification of tumour lipid (2,845 cm−1‐peak) and cholesterol (2,880 cm−1‐peak) content obtained from (F).

Data information: AU, arbitrary unit. Panels (B, C, E) Data are presented as mean values ± SD. Panels (G, H) Centre line corresponds to median of data, top and bottom lines correspond to upper and lower quartiles. Statistical analysis: (B, C) *P‐value < 0.05 using a one‐way ANOVA with a Dunnett's multiple comparisons test. (E) *P‐value < 0.05 using a two‐tailed Student's t‐test. (G, H) Kruskal–Wallis test. Data reproducibility: Panels (A, B, C, D, E) n = 3 independent biological experiments. Panel (F) n = 4 mice per group. Panel (G, H) n = 6,581 (CTL); 12,047 (KO1); 6,493 (KO2) peak intensities that were extracted from four mice per group. CE, Cholesteryl ester; Cer, Ceramide; DAG, diacylglycerol; EV, Empty Vector; LysoPC, lysophosphatidylcholine; LysoPE, lysophosphatidylethanolamine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; SM, sphingomyelin; TG, triglyceride. Source data are available online for this figure.
Figure EV2
Figure EV2. Loss of THEM6 alters lipid homeostasis

  1. Heatmap illustrating the steady‐state levels of significantly regulated lipids in THEM6 KO LNCaP AI cells when compared to CTL (P ≤ 0.05, FC = 1.3). Values are expressed as log2(FC).

  2. Western blot analysis of THEM6 expression in CWR22res cells overexpressing THEM6 (T6 OE). HSC70 was used as a sample loading control.

Data information: Data reproducibility: (A) n = 3 independent biological experiments. (B) representative image from two independent biological experiments. Source data are available online for this figure.
Figure 3
Figure 3. THEM6 interacts with multiple ER membrane components involved in protein transport

  1. Venn diagram highlighting commonly modulated proteins (P‐value ≤ 0.05, FC = 1.3) in THEM6 KO 22rv1 cells (two clones) when compared to CTL. Up‐regulated proteins are on top; Down‐regulated proteins are into brackets.

  2. Enriched cellular components commonly down‐regulated in THEM6 KO 22rv1 cells (two clones) when compared to CTL.

  3. Representative electron microscopy (EM) pictures of CTL and THEM6 KO 22rv1 cells taken at low (left) and high (right) magnification. Red arrows point towards abnormal ER structure. Scale bar represents 500 nm.

  4. Quantification of ER membrane length, plasma membrane length and ER/plasma membrane ratio using the EM pictures from (C).

  5. Immunofluorescence showing co‐localisation of THEM6 and the ER marker calreticulin in 22rv1 cells. Scale bar represents 20 µm.

  6. Prediction of transmembrane domain in the sequence of the THEM6 protein. Topology prediction was performed using the TMHMM server (http://www.cbs.dtu.dk/services/TMHMM).

  7. Western blot analysis of THEM6 expression in cytoplasmic (cyto.), membrane/organelle (memb.) and nuclear fractions (nucl.) of 22rv1 cells. HSC70 and SP1 were used as cytoplasmic and nuclear‐enriched markers, respectively.

  8. Enriched cellular components in THEM6‐interacting proteins following THEM6 pulldown in T6 OE HEK293 cells.

  9. Western blot analysis of THEM6, AMFR, SEC61b and XPO1 expression in CRPC cells following THEM6 immunoprecipitation in CRPC cells.

  10. Western blot analysis of CALX and CALR expression in PCa cells following THEM6 silencing.

Data information: Panels (B, H) Enrichment analysis was performed using the STRING database (http://string‐db.org). Panel (D) Data are presented as mean values ± SD. Statistical analysis: (D) Unpaired t‐test. Data reproducibility: Panel (D) n = 20 cells/condition. Panels (E, G, J) representative image from three independent biological experiments. Panel (I) representative image from two independent biological experiments. Source data are available online for this figure.
Figure EV3
Figure EV3. THEM6 is an ER membrane protein

  1. Representative electron microscopy pictures of THEM6 KO 22rv1 cells. Green and blue arrows point towards enlarged mitochondria and abnormal lysosomal structure, respectively. Scale bar represents 500 nm.

  2. Immunofluorescence showing co‐localisation of THEM6 and the ER marker calreticulin in LNCaP AI cells. Scale bar represents 20 µm.

  3. Immunofluorescence showing distinct localisations for THEM6 and mitochondria in 22rv1 cells. Scale bar represents 20 µm.

  4. Western blot analysis of THEM6 expression in cytoplasmic (cyto.), membrane/organelle (memb.) and nuclear fractions (nucl.) of LNCaP AI cells. HSC70 was used as cytoplasmic‐enriched marker.

  5. Western blot analysis of THEM6 and MYC‐tag expression in HEK293 cells overexpressing a MYC‐tagged version of THEM6 (T6 OE). HSC70 was used as a sample loading control.

  6. Enriched biological processes in THEM6‐interacting proteins following THEM6 pulldown in T6 OE HEK293 cells.

Data information: Panel (F) Enrichment analysis was performed using the STRING database (http://string‐db.org). Data reproducibility: (B, C, D) representative image from 3 independent biological experiments. (E) representative image from two independent biological experiments. Source data are available online for this figure.
Figure 4
Figure 4. Loss of THEM6 affects de novo sterol and fatty acid synthesis

  1. Proteomic analysis highlighting proteins associated with sterol biosynthetic pathway and significantly down‐regulated in THEM6 KO 22rv1 cells when compared to CTL (P‐value ≤ 0.05, FC = 1.3).

  2. RT–qPCR analysis of MVD, FDPS and DHCR7 expression in CTL and THEM6 KO 22rv1 cells. CASC3 was used as a normalising control.

  3. Gene set enrichment plots analysed from THEM6 KO LNCaP AI cells using the GOBP “Sterol homeostasis” gene set.

  4. Labelled desmosterol fraction derived from 13C‐glucose and 13C‐glutamine in CTL and THEM6 KO 22rv1 cells after 72 h of incubation.

  5. Relative isotopologue distribution of desmosterol in CTL and THEM6 KO 22rv1 cells after 72 h of incubation.

  6. Labelled cholesterol fraction derived from 13C‐glucose and 13C‐glutamine in CTL and THEM6 KO CWR22res cells after 72 h of incubation.

  7. Labelled cholesterol fraction derived from 13C‐glucose and 13C‐glutamine in CTL and THEM6 KO MCF‐7 cells after 72 h of incubation.

  8. Pearson's correlation analysis of SQLE, LSS, DHCR7 and DHCR24 with THEM6 using the PRAD TCGA dataset. Results were obtained using the GEPIA website http://gepia.cancer‐pku.cn/.

  9. Differential expression of ACACA in high and low THEM6 tumours according to the PRAD TCGA dataset.

  10. Labelled palmitic, oleic and stearic acid fractions derived from 13C‐glucose and 13C‐glutamine in CTL and THEM6 KO 22rv1 cells after 72 h of incubation.

  11. Relative isotopologue distribution of palmitic acid in CTL and THEM6 KO 22rv1 cells after 72 h of incubation.

Data information: Panels (A, B, D, E, F, G, J, K) Data are presented as mean values ± SD. Panel (I) Centre line corresponds to median of data, top and bottom of box correspond to 90th and 10th percentile, respectively. Whiskers extend to adjacent values (minimum and maximum data points not considered outliers). Statistical analysis: (B, D, E, F, J, K) *P‐value < 0.05 using one‐way ANOVA with a Dunnett's multiple comparisons test. (G) *P‐value < 0.05 using a two‐tailed Student t‐test. (I) two‐tailed Mann–Whitney U‐test. Data reproducibility: Panels (A, B) n = 3 independent biological experiments. Panels (D, E, F, G, J, K) n = 3 independent wells from the same cell culture. Panel (I) n = 225 tumours for THEM6 low and n = 121 tumours for THEM6 high. Source data are available online for this figure.
Figure EV4
Figure EV4. Loss of THEM6 affects de novo sterol and FA synthesis

  1. Total pool of desmosterol in CTL and THEM6 KO 22rv1 cells. Data extracted from Fig 4D and E.

  2. Total pool of cholesterol in CTL and THEM6 KO CWR22res cells. Data extracted from Fig 4F.

  3. Total pool of cholesterol in CTL and THEM6 KO MCF‐7 cells. Data extracted from Fig 4G.

  4. Pearson's correlation analysis of HMGCS1, HMGCR, MVK, IDI1, FDPS, FDFT1, SC5D with THEM6 using the PRAD TCGA dataset. Results were obtained using the GEPIA website http://gepia.cancer‐pku.cn/.

  5. Western blot analysis of SREBP1 (precursor and mature forms) expression in CTL and THEM6 KO CRPC cells. HSC70 was used as a sample loading control.

  6. Total pool of palmitic, oleic and stearic acid in CTL and THEM6 KO 22rv1 cells. Data extracted from Fig 4J and K.

  7. Labelled palmitic, oleic and stearic acid fractions derived from 13C‐glucose and 13C‐glutamine in CTL and THEM6 KO MCF‐7 cells after 72 h of incubation.

  8. Relative isotopologue distribution of palmitic acid in CTL and THEM6 KO MCF‐7 cells after 72 h of incubation.

  9. Total pool of palmitic, oleic and stearic acid in CTL and THEM6 KO 22rv1 cells. Data extracted from (G, H).

Data information: Panels (A, B, C, F, G, H, I) Data are presented as mean values ± SD. Statistical analysis: (A, B, F) One‐way ANOVA with a Dunnett's multiple comparisons test. (C, G, H, I) two‐tailed Student t‐test. Data reproducibility: (A, B, C, F, G, H, I) n = 3 independent wells from the same cell culture. (E) representative image from three independent biological experiments. Source data are available online for this figure.
Figure 5
Figure 5. THEM6‐mediated lipid remodelling is required for UPR activation

  1. Enriched biological processes commonly down‐regulated in THEM6 KO 22rv1 cells (two clones) when compared to CTL.

  2. Proteomic analysis highlighting proteins associated with the ER stress response significantly down‐regulated in THEM6 KO 22rv1 cells when compared to CTL (P‐value ≤ 0.05, FC = 1.3).

  3. Western blot analysis of BIP, XBP1s, ATF4, CHOP and THEM6 expression in CTL and THEM6 KO 22rv1 cells.

  4. Proliferation of CTL and THEM6 KO CRPC cells treated with tunicamycin (2.5 µg/ml) for 72 h. Cell count is normalised to initial number of cells at T0.

  5. Proteomic analysis highlighting ATF4 targets significantly down‐regulated in THEM6 KO LNCaP AI cells when compared to CTL (P‐value ≤ 0.05, FC = 1.3).

  6. Western blot analysis of ATF4 and THEM6 expression in CTL and THEM6 KO LNCaP AI cells.

  7. Western blot analysis of ATF4, CHOP and THEM6 expression in PCa cells following THEM6 silencing.

  8. Differential expression of EIF4G1 and ASNS in high and low THEM6 tumours according to the PRAD TCGA dataset.

  9. Western blot analysis of ATF4 and CHOP expression in CTL and THEM6 KO 22rv1 cells treated with palmitic acid (200 µM) for 48 h.

  10. Western blot analysis of ATF4 and CHOP expression in CTL and THEM6 KO LNCaP AI cells treated with palmitic acid (200 µM) or hexadecylglycerol (50 µM) for 48 h.

Data information: Panels (C, F, G, I, J) HSC70 was used as a sample loading control. Panels (B, D, E) Data are presented as mean values ± SD. Panel (H) Centre line corresponds to median of data, top and bottom of box correspond to 90th and 10th percentile, respectively. Whiskers extend to adjacent values (minimum and maximum data points not considered outliers). Statistical analysis: (D) One‐way ANOVA with a Dunnett's multiple comparisons test. (H) two‐tailed Mann–Whitney U‐test. Data reproducibility: Panels (C, F, G, I, J) representative image from three independent biological experiments. Panels (B, D, E) n = 3 independent biological experiments. Panel (H) n = 225 tumours for THEM6 low and n = 121 tumours for THEM6 high. Source data are available online for this figure.
Figure EV5
Figure EV5. THEM6 regulates UPR activation in CRPC

  1. Venn diagram highlighting commonly modulated proteins (P‐value ≤ 0.05, FC = 1.3) in THEM6 KO LNCaP AI cells (two clones) when compared to CTL. Up‐regulated proteins are on top; Down‐regulated proteins are into brackets.

  2. Western blot analysis of BIP, XBP1s and THEM6 expression in CTL and THEM6 KO LNCaP AI cells.

  3. Western blot analysis of p‐IRE1α, p‐PERK and ATF6 expression in CTL and THEM6 KO 22rv1 cells treated or not with tunicamycin.

  4. Western blot analysis of p‐IRE1α, p‐PERK and ATF6 expression in CTL and THEM6 KO LNCaP AI cells treated or not with tunicamycin.

Data information: Panels (B, C, D) HSC70 was used as a sample loading control. Data reproducibility: (B, C, D) representative image from three independent biological experiments. Source data are available online for this figure.
Figure 6
Figure 6. THEM6 is a clinically relevant target in CRPC
  1. A

    Gene expression analysis of THEM6/c8orf55 in normal and tumoural prostate tissues according to the PRAD TCGA dataset (n = 489).

  2. B

    Gene expression analysis of THEM6/c8orf55 in benign, localised and metastatic tumoural prostate tissues according to the GSE35988 dataset (n = 122).

  3. C

    Kaplan–Meier progression‐free survival analysis of PCa patients stratified according high and low THEM6 expression using the PRAD TCGA dataset.

  4. D

    Kaplan–Meier recurrence‐free survival analysis of PCa patients stratified according to median THEM6 expression using the GSE21034 dataset (n = 179).

  5. E

    IHC staining of THEM6 expression in treatment naïve, NHT‐treated, CRPC and NEPC tumours. Scale bar represents 100 µm.

  6. F

    Quantification of THEM6 staining in PCa tissue samples.

  7. G, H

    Quantification of THEM6 expression in PCa tissue samples according to Gleason score (G) and metastatic status (H) in the patients analysed in (F).

  8. I, J

    Kaplan–Meier recurrence‐free (I) and overall (J) survival analysis of PCa patients stratified according to median THEM6 expression.

  9. K

    Quantification of THEM6 expression in PCa tissue samples according to Ki67 expression in the patients analysed in (F).

  10. L

    Quantification of THEM6 expression in PCa tissue samples according to Ki67 expression in the patients analysed in (I, J).

  11. M

    Volcano plot of the differentially modulated genes in PCa patients from the PRAD TCGA stratified according to THEM6 expression. Red dots represent the UPR‐related genes extracted from the UPR‐gene signature obtained from (Adamson et al, 2016).

  12. N

    Gene set enrichment plot analysed from PCa patients of the PRAD TCGA dataset using the UPR gene signature obtained from (Adamson et al, 2016).

Data information: Panels (A, B) Center line corresponds to median of data, top and bottom of box correspond to 75th and 25th percentile, respectively. Whiskers extend to adjacent values (minimum and maximum data points not considered outliers). Panel (F) Centre line corresponds to median of data, top and bottom lines correspond to upper and lower quartiles. Panels (G, H, K, L) Centre line corresponds to median of data, top and bottom of box correspond to 90th and 10th percentile, respectively. Whiskers extend to adjacent values (minimum and maximum data points not considered outliers). Statistical analysis: (A, B) pairwise ANOVA. (C, D, I, J) logrank test. (F) One‐way ANOVA with a Dunnett's multiple comparisons test. (G, H, K, L) two‐tailed Mann–Whitney U‐test. Data reproducibility: Panels (A, C) n = 489 tumours. Panel (B) n = 122 tumours. Panel (D) n = 179. Panels (E, F) n = 132; 90; 66; 137; 44; 30 tumours for Untreated; NHT 1–3; NHT4–6; NHT > 7; CRPC; NEPC respectively. Panel (G) n = 99 tumours for Gleason score ≤ 7 and n = 63 tumours for Gleason score > 7. Panel (H) n = 151 tumours for non‐metastatic patients and n = 76 tumours for metastatic patients. Panels (I, J) n = 35 tumours for THEM6 low and n = 34 tumours for THEM6 high. Panel (K) n = 269 tumours for Ki67 low and n = 270 tumours for Ki67 high. (L) n = 35 tumours for Ki67 low and n = 29 tumours for Ki67 high. Panel (M) n = 489 tumours. Source data are available online for this figure.
Figure EV6
Figure EV6. THEM6 is a clinically relevant target in CRPC
  1. A

    Gene expression analysis of THEM6/c8orf55 in normal prostate tissues, primary tumours, distant metastases and PCa cell lines according to the GSE21034 dataset (n = 179).

  2. B

    Percentage of PCa patients showing genomic alteration (copy number gain or amplification) for THEM6 in publicly available datasets of PCa. Analysis was performed using the cbioportal website https://www.cbioportal.org/.

  3. C

    High magnification pictures of THEM6 staining in NHT‐treated and CRPC tumours.

  4. D, E

    Quantification of THEM6 expression in PCa tissue samples according to T‐stage (D) and cancer recurrence (E).

Data information: Panel (A) Center line corresponds to median of data, top and bottom of box correspond to 75th and 25th percentile, respectively. Whiskers extend to adjacent values (minimum and maximum data points not considered outliers). Panels (D, E) Center line corresponds to median of data, top and bottom of box correspond to 90th and 10th percentile, respectively. Whiskers extend to adjacent values (minimum and maximum data points not considered outliers). Statistical analysis: (A) pairwise ANOVA. (D, E) two‐tailed Mann–Whitney U‐test. Data reproducibility: (D) n = 129 tumours for T stage score < 3 and n = 135 tumours for T stage score ≥ 3. (E) n = 91 for disease‐free patients and n = 136 for recurred patients. Source data are available online for this figure.
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