Paper - Review

DOI: 10.1016/j.ccell.2020.08.009

Abstract

An outgrowth
← of therapy-resistant prostate cancers
← with enhanced metastatic potential
→ may be triggered
← by inhibitors of (androgen receptor) signaling

Contents

First-line treatment
← for metastatic PCa (← Prostate Cancer)
→ ADT (← androgen deprivation therapy)

CRPC
← castration-resistance PCa
→ is still driven ← by hormonal signaling

CRPC patients
→ develop secondary resistance
← paired with enhanced metastatic capability

Mounting evidence
→ support (epigenetic events)
→ as mechanisms → for PCa trans-differentiation
→ to an AR-indifferent state

DNA methylation
→ plays a significant role
← in mediating these mechanisms
← in PCa among other cancers

EZH2
← Enhancer of zeste homolog 2
→ tri-methylate histone H3K27
→ induces gene sliencing
∴ with poor survival in PCa

EZH2
→ is the catalytic core subunit
← PRC2 (← polycomb repressive complex 2)

Activity of EZH2
→ relies on
← 1⃣ its cystine-rich region 2⃣ its SET domain

1⃣ Physiological 2⃣ Cellular functions ← of EZH2
→ are manifold
← including 1⃣ mammalian development 2⃣ genomic imprinting

EZH2 induces
→ 1⃣ anchorage-independent colony formation 2⃣ cell invasion
← in cancer ❗
∴ EZH2 linked → to self-renewal
← in 1⃣ poorly differentiated cancer 2⃣ cancer stem cells

Gain-of-function mutations
← in the EZH2 SET domain
→ reported ← in a variety of cancers
← e.g. 1⃣ non0Hodgkin's lymphoma 2⃣ melanoma

The exact number (← of NEPC cases)
← harboring elevated levels of EZH2
→ is still unclear ❓
∵ the lack of epigenomic data
← in this context

∴ The underlying mechanisms
← that orchestrate EZH2 expresion ← in CRPC
→ remains elusive
→ is needed to pin down → the clinical relevance of EZH2 ← in PCa

Inversely correlated
← 1⃣ EZH2-mediated H3K27me3 2⃣ SETD2-mediated H3K36me3
→ are enzymatically interwined

Depletion (← of the HMT SETD2)
→ has been reported → in advanced PCa
∴ Emphasizing its role ← in disease progression

Assessed tumor-suppressive function ← of SETD2
Discovered EZH2 → its direct non-histone substrates
∴ Triggering a Smurf2 E3 ligase-dependent degradation

These finding were supported
← by 1⃣ enginerring SETD2-deficient mice 2⃣ mice harboring EZH2 mutate at the K735R
→ to prevent SETD2-mediated methylation of EZH2

In these mice
→ observed accelerated (tumor progression)
← compared to control mice
∴ an even large network of pathways
← that feeding the oncogenic role ← of EZH2

Clinical implications
→ were exemplified
← by 1⃣ the use of cancer-associated missense mutated SETD2 variants 2⃣ manifested at the R1523 residue

The forced expression
← of (the mutant R1523H)
→ led to abrogated EZH2 interaction
← without ❌ affecting the H3K36me3 activity of SETD2

1⃣ applied → a chemical screen
→ on ADT-insensitive PCa cells
2⃣ identified → a network driven
← by the AMP-dependent kinase
∵ to study → upstream mechanisms governing SETD2 expression

❗: an AMPK agonist → could trigger
→ methylation of the EZH2 lysine-residue K735

Treatment
← with the AMPK agonist metformin
→ reduced (colony formation efficiency) ← of CRPC organoids
→ impaired (tumor growth) ← in patient-derived xenografts

EZH2 levels
→ decreased upon metformin treatment
∴ results of reduced (colony formation) efficiency

Impaired interaction
← between 1⃣ EZH2 2⃣ SUZ12
❗: 1⃣ SETD2 2⃣ EZH2 methylation levels → were increased

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