CD38 is methylated in prostate cancer and regulates extracellular NAD

Jack Mottahedeh; Michael C Haffner; Tristan R Grogan; Takao Hashimoto; Preston D Crowell; Himisha Beltran; Andrea Sboner; Rohan Bareja; David Esopi; William B Isaacs; Srinivasan Yegnasubramanian; Matthew B Rettig; David A Elashoff; Elizabeth A Platz; Angelo M De Marzo; Michael A Teitell; Andrew S Goldstein

doi:10.1186/s40170-018-0186-3

CD38 is methylated in prostate cancer and regulates extracellular NAD

Cancer Metab. 2018 Sep 21:6:13. doi: 10.1186/s40170-018-0186-3. eCollection 2018.

Authors

Jack Mottahedeh¹, Michael C Haffner^{2

3}, Tristan R Grogan⁴, Takao Hashimoto¹, Preston D Crowell⁵, Himisha Beltran^{6

7}, Andrea Sboner^{7

8

9}, Rohan Bareja^{7

9

10}, David Esopi², William B Isaacs^{2

3

11}, Srinivasan Yegnasubramanian^{2

12}, Matthew B Rettig^{13

14

15

16}, David A Elashoff^{4

15}, Elizabeth A Platz^{2

17

18

19}, Angelo M De Marzo^{2

3

11

18}, Michael A Teitell^{15

20

21

22}, Andrew S Goldstein^{1

14

15

21

22}

Affiliations

¹ 1Department of Molecular, Cell & Developmental Biology, University of California Los Angeles, Los Angeles, CA USA.
² 2Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD USA.
³ 3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA.
⁴ 4Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, CA USA.
⁵ 5Molecular Biology Interdepartmental Program, University of California Los Angeles, Los Angeles, CA USA.
⁶ 6Department of Medicine, Division of Medical Oncology, Weill Cornell Medicine, New York, NY USA.
⁷ 7Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY USA.
⁸ 8Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY USA.
⁹ 9Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY USA.
¹⁰ 10Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY USA.
¹¹ 11James Buchanan Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, MD USA.
¹² 12Departments of Oncology, Pathology, and Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD USA.
¹³ 13Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA USA.
¹⁴ 14Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA USA.
¹⁵ 15Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA USA.
¹⁶ 16Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA USA.
¹⁷ 17Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.
¹⁸ 18Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD USA.
¹⁹ 19Department of Urology and the James Buchanan Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, MD USA.
²⁰ 20Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA USA.
²¹ 21Broad Stem Cell Research Center, University of California Los Angeles, Los Angeles, CA USA.
²² 22Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA USA.

Abstract

Background: Cancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD⁺) which is maintained by a balance of NAD⁺ hydrolase activity and NAD⁺ salvage activity. We recently reported that human prostate cancer can be initiated following oncogene expression in progenitor-like luminal cells marked by low expression of the NAD⁺-consuming enzyme CD38. CD38 expression is reduced in prostate cancer compared to benign prostate, suggesting that tumor cells may reduce CD38 expression in order to enhance pools of NAD⁺. However, little is known about how CD38 expression is repressed in advanced prostate cancer and whether CD38 plays a role in regulating NAD⁺ levels in prostate epithelial cells.

Methods: CD38 expression, its association with recurrence after prostatectomy for clinically localized prostate cancer, and DNA methylation of the CD38 promoter were evaluated in human prostate tissues representing various stages of disease progression. CD38 was inducibly over-expressed in benign and malignant human prostate cell lines in order to determine the effects on cell proliferation and levels of NAD⁺ and NADH. NAD⁺ and NADH were also measured in urogenital tissues from wild-type and CD38 knockout mice.

Results: CD38 mRNA expression was reduced in metastatic castration-resistant prostate cancer compared to localized prostate cancer. In a large cohort of men undergoing radical prostatectomy, CD38 protein expression was inversely correlated with recurrence. We identified methylation of the CD38 promoter in primary and metastatic prostate cancer. Over-expression of wild-type CD38, but not an NAD⁺ hydrolase-deficient mutant, depleted extracellular NAD⁺ levels in benign and malignant prostate cell lines. However, expression of CD38 did not significantly alter intracellular NAD⁺ levels in human prostate cell lines grown in vitro and in urogenital tissues isolated from wild-type and CD38 knockout mice.

Conclusions: CD38 protein expression in prostate cancer is associated with risk of recurrence. Methylation results suggest that CD38 is epigenetically regulated in localized and metastatic prostate cancer tissues. Our study provides support for CD38 as a regulator of extracellular, but not intracellular, NAD⁺ in epithelial cells. These findings suggest that repression of CD38 by methylation may serve to increase the availability of extracellular NAD⁺ in prostate cancer tissues.

Keywords: CD38; Methylation; NAD+; Prostate.

Abstract

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