# A Novel Druggable Epigenetic Vulnerability Pathway in HCC

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $585,065

## Abstract

PROJECT SUMMARY
Hepatocellular carcinoma (HCC) accounts for nearly 29,000 deaths annually in the United States alone.
However, the molecular mechanisms that drive HCC development remain elusive and current HCC therapies
provide negligible clinical benefit. Factors that epigenetically silence an HCC tumor suppressor gene have the
potential to promote tumorigenesis and thus may provide novel drug targets for HCC therapies. T o discover
such factors, we performed an innovative genome-wide human RNA interference (RNAi) screen to identify
factors that mediate epigenetic silencing of the HCC tumor suppressor gene Hedgehog-Interacting Protein
(HHIP). HHIP is a negative regulator of Sonic hedgehog (SHH) signaling and loss of HHIP due to epigenetic
silencing aberrantly activates SHH signaling, which has been proposed to promote tumor growth in multiple
cancers including HCC. One of the factors identified in our screen is CDC-like kinase 1 (CLK1), a dual
specificity protein kinase that phosphorylates serine/arginine-rich proteins involved in pre-mRNA splicing. We
found that CLK1 transforms cultured immortalized hepatocytes and promotes HCC tumor growth in mouse
subcutaneous xenografts, and these effects are dependent upon CLK1 protein kinase activity. Notably,
epigenetic silencing of HHIP and CLK1 overexpression occur frequently in HCC patient samples, supporting
the clinical relevance of our results. Based on these collective findings, we hypothesize that CLK1 is a driver of
HCC and functions by epigenetically silencing the tumor suppressor HHIP. The results of the experiments
proposed in this application will establish the role of CLK1 as a driver of HCC, determine the mechanism by
which CLK1 promotes tumor growth, and evaluate CLK1 as a drug target for HCC therapy. In Aim 1, we will
establish the role of CLK1 in initiation and progression of hepatic tumorigenesis using a series of
complementary mouse models that recapitulate characteristic features of HCC. In Aim 2, we will test our
hypothesis that CLK1 promotes hepatic tumor growth through epigenetic silencing of HHIP, resulting in
aberrant activation of SHH signaling. We will also investigate other mechanisms by which CLK1 may promote
tumor growth. In Aim 3, we will evaluate CLK1 as a novel drug target for the development of HCC therapeutics.
In preliminary experiments, we have found that inhibition of CLK1 enhances natural killer (NK) cell-mediated
eradication of HCC cells. Therefore, we predict that reactivation of HHIP by pharmacological inhibition of CLK1
will: (1) directly inhibit tumor growth by blocking oncogenic SHH signaling, and (2) augment NK cell-mediated
eradication of tumor cells. To test these predictions we will determine whether the highly specific CLK1 small
molecule inhibitor KH-CB19 can effectively inhibit growth of hepatic tumors and enhance the ability of NK cells
to eradicate tumors using a complementary series of immunocompromised and immunocompetent mouse
models of HCC. Collec...

## Key facts

- **NIH application ID:** 10133462
- **Project number:** 5R01CA218008-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** MICHAEL R GREEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $585,065
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133462

## Citation

> US National Institutes of Health, RePORTER application 10133462, A Novel Druggable Epigenetic Vulnerability Pathway in HCC (5R01CA218008-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10133462. Licensed CC0.

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