SETD2 and Clear Cell Renal Cell Carcinoma

Abby Kepley

SETD2 is a Histone Methyltransferase of H3K36me3

Post-translational modifications of H3K36 are important in regulating DNA

structure and expression throughout the genome

Multiple domains within SETD2 contribute to its enzymatic function

S-adenosylmethionine (SAM)

SETD2/HYPB is required for murine embryonic vascular remodeling

Whole-mount IHC with PECAM-1 antibody

In vitro tube formation assay with siRNA

Clear Cell Renal Cell Carcinoma is the most common form of RCC

• ~75% of renal cell carcinomas are ccRCC

• There are both hereditary and sporadic forms

• 1/3 of patients present with locally advanced or metastatic disease

Tumor suppressors VHL, BAP1, SETD2, and PBRM1 are commonly mutated in

ccRCC

Loss of SETD2 function leads to impaired signaling in the DNA damage response

It also leads to inactivation of p53

The role of SETD2 in homologous repair

Treatment options for ccRCC

• There has yet to be a targeted therapy for histone methyltransferases to reach clinical trials.

• Current Therapies Include:• Local: nephrectomy, EBRT• Cytokine Therapy: interferon-alpha, IL-2• Targeted: Sunitinib, Sorafenib

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