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Reference Guide
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KLK3
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KLK3

The KLK3 gene encodes prostate-specific antigen (PSA), a serine protease secreted by the prostate gland that plays a key role in semen liquefaction and is a widely used biomarker for prostate cancer. 

While PSA testing is a cornerstone of prostate cancer screening and monitoring, its interpretation requires clinical context due to elevations in benign conditions and individual genetic variation.

What is KLK3 (Kallikrein-Related Peptidase 3 / Prostate-Specific Antigen)?

The KLK3 gene, short for Kallikrein-Related Peptidase 3, is located on chromosome 19q13.33

It encodes a protein known as Prostate-Specific Antigen (PSA). PSA is a serine protease—a type of enzyme that breaks down proteins—and is produced almost entirely by the epithelial cells of the prostate gland.

In the body, PSA is secreted into seminal fluid, where it plays a key role in semen liquefaction by breaking down proteins that cause seminal coagulation. This helps sperm move more freely after ejaculation. 

While most PSA remains in the prostate or semen, small amounts circulate in the bloodstream, and clinicians measure these in PSA blood tests.

When is KLK3/PSA Testing Clinically Relevant?

PSA testing may be relevant in the following scenario

Screening, Diagnosis, and Monitoring of Prostate Cancer

The most common use of PSA testing is in the detection and monitoring of prostate cancer.  An elevated PSA can lead to further evaluation, such as prostate MRI or biopsy.

PSA is also used to track response to treatment after surgery, radiation, or hormone therapy: a rising PSA after treatment may indicate cancer recurrence.

PSA Screening Controversy

While PSA testing has helped detect prostate cancer early, its routine use remains debated: for example, PSA is not cancer-specific and can be elevated in non-cancer conditions.

Additionally, overdiagnosis of slow-growing cancers can lead to unnecessary treatment. Guidelines differ by organization, so shared decision-making with patients is essential.

PSA Can Be Elevated in Non-Cancer Conditions

Elevated PSA levels can also occur with:

  • Benign prostatic hyperplasia (BPH) – prostate gland enlargement.
  • Prostatitis – inflammation of the prostate.
  • Recent ejaculation or prostate manipulation – such as during a digital rectal exam or cystoscopy.

PSA Testing: Process and Procedure

PSA testing is primarily used for the early detection, monitoring, and risk stratification of prostate cancer. While highly sensitive, it is not cancer-specific and must be interpreted in clinical context.

Who Should Be Tested

Guidelines vary according to sources, but general recommendations may include:

  • Baseline testing: Suggested at age 40–45
  • Annual testing: Recommended for high-risk individuals starting at age 45 (e.g., African ancestry, family history, BRCA mutations)
  • Average risk: Begin testing by age 50 after informed discussion
  • Discontinue: For men over 75 or with <10-year life expectancy

Pre-Test Counseling

Testing should follow shared decision-making. Discuss the risks of overdiagnosis, overtreatment, and false positives, particularly in men with benign prostatic conditions.

Test Procedure

Test procedure typically includes:

  • Blood draw for serum PSA measurement
  • Avoid recent ejaculation, digital rectal exam, or urologic procedures beforehand, as they may elevate PSA
  • Repeat testing is needed to confirm elevated results (≥2 tests)

What Do Elevated KLK3/PSA Levels Mean?

Higher PSA levels may suggest prostate cancer, but they are not specific and require clinical context. Most men with elevated PSA do not have cancer; a biopsy is needed for diagnosis.

Factors That Influence PSA Levels

The following factors are known to influence PSA levels:

  • Age
  • Race/ethnicity
  • Prostate size
  • Medications (e.g., finasteride)
  • KLK3 gene variants (see below)

Tools That Improve PSA Interpretation

  • PSA Velocity: How quickly PSA rises over time. Faster increases may suggest more aggressive cancer. However, this is not always accepted as a reliable tool.
  • PSA Density: PSA level divided by prostate volume. Higher density raises suspicion.
  • % Free PSA: A lower percentage of unbound (free) PSA is more associated with cancer.

What Do Low KLK3/PSA Levels Mean?

Low PSA levels usually mean a lower risk of prostate cancer, but do not rule it out completely. Some men with prostate cancer may have low PSA. 

After successful prostate cancer treatment, PSA should fall to very low or undetectable levels. A rising PSA post-treatment can be an early sign of recurrence.

Molecular and Genetic Insights into KLK3

The KLK3 gene is located on chromosome 19q13.33 and is part of the kallikrein gene family. It is regulated by androgens, including dihydrotestosterone (DHT), through the androgen receptor (AR) pathway.

PSA exists in multiple forms in the blood:

  • Free PSA (fPSA) – active enzyme
  • Complexed PSA (cPSA) – bound to blood proteins
  • Total PSA (tPSA) = fPSA + cPSA

KLK3 Genetic Variants and Clinical Relevance

Several single nucleotide polymorphisms (SNPs) in the KLK3 gene affect PSA levels and cancer risk, including:

These variants can explain up to 40–45% of individual PSA level differences, even in men without prostate disease.

Some studies suggest that combining KLK3 SNPs with other genetic markers may help:

  • Distinguish aggressive from indolent prostate cancers
  • Refine risk models to reduce false positives in screening
  • Predict PSA behavior decades before disease develops

KLK3 in Cancer Biology and Angiogenesis

In prostate cancer, KLK3 (PSA) has complex roles: for example, it may suppress tumor growth by inhibiting new blood vessel formation (anti-angiogenic).

However, KLK3 can also activate VEGF-C and VEGF-D, which promote angiogenesis and lymphangiogenesis, potentially aiding metastasis in advanced cancers.

The impact of KLK3 on tumor progression appears to depend on the tumor environment, androgen signaling, and the balance of VEGF isoforms present.

Pathways and Expression

KLK3 is involved in:

  • Androgen receptor (AR) signaling
  • Rho GTPase pathways (cell movement, invasion)
  • Insulin-like growth factor (IGF) regulation

It is highly expressed in prostate epithelial cells and secreted into seminal plasma. It can also be detected at low levels in nucleus and cytosol, though its primary action is extracellular.

KLK3 Genetic Testing: Test Procedure and Interpretation

Testing for KLK3 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for KLK3 genetic testing are considered to be without mutations that can alter the activity of the KLK3 proteins.

Clinical Takeaways for Clinicians

KLK3 (PSA) testing remains a cornerstone of prostate cancer care but requires contextual interpretation.

Genetic variation in KLK3 affects PSA levels and prostate cancer risk. Incorporating genetic data may improve screening accuracy.

PSA metrics such as velocity, density, and free/total ratios enhance diagnostic value.

While PSA is an essential diagnostic and monitoring tool, it should not be used in isolation. Shared decision-making with patients is key.

Understanding the biological, genetic, and clinical dimensions of KLK3 will help clinicians use PSA more effectively and reduce unnecessary interventions.

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See References

David MK, Leslie SW. Prostate-Specific Antigen. [Updated 2024 Sep 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557495/

Dawood, M. F., Khalaf, S. M., & Suleiman, A. A. (2017). Physiological variables and molecular study of KLK2 and KLK3 among patient with benign prostatic hyperplasia. Alexandria Journal of Medicine, 54(3), 203–206. https://doi.org/10.1016/j.ajme.2017.03.001

Gene Database. (2025). KLK3 Gene - GeneCards | KLK3 Protein | KLK3 Antibody. Genecards.org. https://www.genecards.org/cgi-bin/carddisp.pl?gene=KLK3

Jain MA, Leslie SW, Sapra A. Prostate Cancer Screening. [Updated 2023 Oct 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556081/

KLK3 kallikrein related peptidase 3 [Homo sapiens (human)] - Gene - NCBI. (n.d.). Www.ncbi.nlm.nih.gov. https://www.ncbi.nlm.nih.gov/gene/354

Koistinen H, Künnapuu J, Jeltsch M. KLK3 in the Regulation of Angiogenesis-Tumorigenic or Not? Int J Mol Sci. 2021 Dec 17;22(24):13545. doi: 10.3390/ijms222413545. PMID: 34948344; PMCID: PMC8704207.

Li H, Fei X, Shen Y, Wu Z. Association of gene polymorphisms of KLK3 and prostate cancer: A meta-analysis. Adv Clin Exp Med. 2020;29(8):1001–1009. doi:10.17219/acem/121521

Lin HY, Huang PY, Cheng CH, Tung HY, Fang Z, Berglund AE, Chen A, French-Kwawu J, Harris D, Pow-Sang J, Yamoah K, Cleveland JL, Awasthi S, Rounbehler RJ, Gerke T, Dhillon J, Eeles R, Kote-Jarai Z, Muir K; UKGPCS collaborators; Schleutker J, Pashayan N; APCB (Australian Prostate Cancer BioResource); Neal DE, Nielsen SF, Nordestgaard BG, Gronberg H, Wiklund F, Giles GG, Haiman CA, Travis RC, Stanford JL, Kibel AS, Cybulski C, Khaw KT, Maier C, Thibodeau SN, Teixeira MR, Cannon-Albright L, Brenner H, Kaneva R, Pandha H; PRACTICAL consortium; Srinivasan S, Clements J, Batra J, Park JY. KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness. Sci Rep. 2021 Apr 29;11(1):9264. doi: 10.1038/s41598-021-85169-7. PMID: 33927218; PMCID: PMC8084951.

Sävblom C, Halldén C, Cronin AM, Säll T, Savage C, Vertosick EA, Klein RJ, Giwercman A, Lilja H. Genetic variation in KLK2 and KLK3 is associated with concentrations of hK2 and PSA in serum and seminal plasma in young men. Clin Chem. 2014 Mar;60(3):490-9. doi: 10.1373/clinchem.2013.211219. Epub 2013 Nov 22. PMID: 24270797; PMCID: PMC3943614.

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