# A novel oncogenic axis in African American prostate cancer

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2021 · —

## Abstract

Prostate cancer (PCa) is the most common malignancy in veterans. African American (AA) men have the
highest incidence of PCa in the world and are twice as likely to die of PCa as European American (EA) men.
Studies have shown that there is a higher mortality from PCa in AA men even after adjustment for
socioeconomic factors. Thus, biological factors play a significant role in the disparity in incidence and mortality
from PCa in AA men.
We have carried out the largest existing combined study of gene expression and copy number alterations in AA
PCa and matched benign tissues in order to elucidate novel mechanisms of carcinogenesis in AA PCa. We
have defined a region of loss on 4p16.3 that it is lost more commonly in AA PCa. Detailed analysis showed
that RGS12 is the target of these deletion events. RGS12 (regulator of G-protein signaling 12) is a negative
regulator of G-protein signaling that has not been previously implicated as a tumor suppressor gene. Analysis
of PCa tissues from AA and EA men and in vitro and in vivo studies have shown that RGS12 is a tumor
suppressor gene that is preferentially decreased in AA PCa.
RGS12 inhibits Gα12 and Gα13 SRF mediated transcription. G-protein coupled receptors (GPCRs) that are
upstream of Gα12 and/or Gα13 have been implicated in PCa progression. Similarly, RGS12 binds with high
affinity to the CXCL8 (IL-8) receptor CXCR2, which is a GPCR. Ligand binding to CXCR2 can activate multiple
pathways including PI3K/AKT, MAPK, PLC and Rho. There is a very extensive literature implicating CXCL8,
other CXCR2 binding chemokines and/or CXCR2 in PCa. However, the extent to which RGS12 can inhibit the
specific pathways involving Gα12, Gα13 and CXCR2 in PCa and the biological impact of this inhibition is not
known, but is clearly potentially relevant to the tumor suppressor activities of RGS12 in PCa.
Knockdown of RGS12 results in increased phosphorylation of HSP27 and ATF2. These two pathways are well
known to be linked to oncogenic transformation and therapy resistance. In addition, RGS12 expression
markedly decreases both androgen receptor and AKT protein expression. PCa tumors shows marked
increases in MNX1 protein expression compared to benign prostate in AA PCa but much smaller increases in
EA PCa. In vitro and in vivo studies have shown that MNX1 is an oncogene. Thus, RGS12 is a tumor
suppressor whose loss results in activation of multiple important pathways (AR, AKT, HSP27, ATF2, MNX1)
linked to oncogenic transformation and therapy resistance.
In Aim 1 we will examine the pathways mediating RGS12 tumor suppression. We will systematically examine
signaling pathways induced by RGS12 loss including known RGS12 targets Gα12, Gα13 and CXCR2 signaling
as well as the more distal signaling pathways we have identified in our preliminary studies. In Aim 2 we will
further examine the phenotypic effects of decreased RGS12. Several pathways activated by loss of RGS12
have been associated with increased invasion and metastasis...

## Key facts

- **NIH application ID:** 10158403
- **Project number:** 5I01BX002560-07
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** Michael M Ittmann
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-10-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158403

## Citation

> US National Institutes of Health, RePORTER application 10158403, A novel oncogenic axis in African American prostate cancer (5I01BX002560-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10158403. Licensed CC0.

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