Hypermethylation-mediated transcriptional repression of TMPRSS2 in androgen receptor-negative prostate cancer cells

Mingliang Chu1, Yunli Chang1, Naitao Wang2

  • 1State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.

Insights

DNA methylation influences prostate cancer progression by regulating TMPRSS2 gene expression. High DNA methyltransferases 1 (DNMT1) levels in AR-negative prostate cancer cells lead to TMPRSS2 hypermethylation and repression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Prostate cancer is a prevalent malignancy in men, with androgen receptor (AR) signaling driving its progression.
  • TMPRSS2, an AR signaling downstream gene, is implicated in prostate carcinogenesis.
  • DNA methylation is a critical epigenetic mechanism regulating gene expression.

Purpose of the Study:

  • To investigate the role of DNA methylation in regulating TMPRSS2 expression in prostate cancer.
  • To explore the relationship between androgen receptor status, TMPRSS2 methylation, and gene expression.
  • To identify potential mechanisms underlying TMPRSS2 transcriptional repression in AR-negative prostate cancer cells.

Main Methods:

  • Analysis of TMPRSS2 expression and DNA methylation levels in AR-positive and AR-negative prostate cancer cells.
  • Treatment of AR-negative cells with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine.
  • Assessment of DNA methyltransferases 1 (DNMT1) levels in relation to TMPRSS2 methylation and expression.

Main Results:

  • AR-negative prostate cancer cells exhibited low TMPRSS2 expression and hypermethylation.
  • AR-positive prostate cancer cells showed high TMPRSS2 expression and hypomethylation.
  • Inhibition of DNA methylation with 5-Aza-2'-deoxycytidine restored TMPRSS2 expression in AR-negative cells.
  • Elevated DNMT1 levels were observed in AR-negative cells with hypermethylated and lowly expressed TMPRSS2.

Conclusions:

  • DNA methylation, potentially mediated by high DNMT1 levels, plays a significant role in TMPRSS2 transcriptional repression in AR-negative prostate cancer.
  • These findings highlight a novel epigenetic mechanism regulating TMPRSS2 in prostate cancer progression.

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.0K
Epigenetic Regulation01:46

Epigenetic Regulation

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
28.7K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.5K
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
6.1K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.6K
MicroRNAs01:22

MicroRNAs

MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After...
21.1K