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Page 241 Huang et al. J Transl Genet Genom 2021;5:240-9 https://dx.doi.org/10.20517/jtgg.2021.14

Keywords: HSD3B1, germline, prostate cancer, androgen deprivation therapy, castration-resistant prostate cancer,
abiraterone, predictive biomarker, multienzyme complexes, patient stratification, omics

INTRODUCTION
It is widely accepted that androgen and androgen receptor (AR) play an important role in the occurrence
[1]
and progression of prostate cancer (PCa) . Androgen deprivation therapy (ADT) via medical or surgical
castration, which has been applied since 1941 , is the principal therapeutic strategy to advanced prostate
[2]
[3-5]
cancer. The general clinical efficiency of ADT depends on its blockage of gonadal androgen . However,
the development from castrate-sensitive prostate cancer (CSPC) to castrate-resistant prostate cancer
[4]
(CRPC) is eventually inevitable . One of the key mechanisms is the intertumoral synthesis of androgen,
including testosterone and dihydrotestosterone (DHT), which originate from adrenal precursor steroids,
[6,7]
such as dehydroepiandrosterone (DHEA) . The androgen synthesis is considered to induce the
reactivation of AR. When the disease finally progresses to the state of CRPC, it becomes highly lethal. To
solve this clinical problem, next-generation hormone therapies were introduced nearly a decade ago . Since
[8]
then, the PCa prognosis is noted to be largely improved by several new drugs such as docetaxel (a
microtubule inhibitor), abiraterone (a selective inhibitor of cytochrome P450 17A1 (CYP17A1), which is a
key enzyme in androgen synthesis), and enzalutamide (a targeted androgen receptor inhibitor) [9-11] .

In terms of the intertumoral androgen synthesis, several key enzymes and genes in the synthetic process are
identified as potential targets for diagnosis or treatment. One of them is 3β-hydroxysteroid dehydrogenase
isoenzyme-1 (3βHSD1, encoded by HSD3B1), which catalyzes the rate-limiting step in the metabolic
conversion from DHEA to testosterone and DHT in the adrenal gland . A specific germline missense-
[12]
encoding variant of HSD3B1(1245A>C, rs1047303) leads to a divergence of enzyme level and downstream
androgen synthesis. HSD3B1(1245A) is known as an adrenal-restrictive allele as it codes an enzyme that is
degraded more rapidly, while HSD3B1(1245C), an adrenal-permissive allele, codes a stable enzyme resistant
to proteasomal degradation that promotes robust conversion from DHEA to DHT [13,14] . A series of studies
indicated that genetic variants in HSD3B1 are associated with the progression of PCa and resistance of
ADT. In this review, the homozygous variant genotype is referred to as HSD3B1 (CC), while the
heterozygous genotype and homozygous wild type are referred to as HSD3B1 (AC) and HSD3B1 (AA),
respectively.

In this review, we summarize the published studies regarding the association between HSD3B1 and the
clinical management of PCa, including both CSPC and CRPC. We also discuss the contemporary
significance of HSD3B1 and its potential value in the therapeutic decision in PCa.

EVIDENCE SYNTHESIS
We searched the published research articles using the keywords “prostate cancer” and “HSD3B1”, in
PubMed and Embase database. In total, 45 results were found. After review of the abstracts and full articles,
16 original research articles were finally included in this review.

HSD3B1(1245C) promotes resistance to ADT and development to CRPC
Recently, plenty of evidence shows that PCa patients carrying HSD3B1(1245C) variant were more likely to
become resistant to ADT and progress to CRPC. This variant was also reported to be associated with worse
survival outcome for patients with PCa treated with ADT, especially for those with low-volume diseases.